Long Noncoding RNAs and Circular RNAs Regulate AKT and Its Effectors to Control Cell Functions of Cancer Cells

AKT serine-threonine kinase (AKT) and its effectors are essential for maintaining cell proliferation, apoptosis, autophagy, endoplasmic reticulum (ER) stress, mitochondrial morphogenesis (fission/fusion), ferroptosis, necroptosis, DNA damage response (damage and repair), senescence, and migration of cancer cells. Several lncRNAs and circRNAs also regulate the expression of these functions by numerous pathways. However, the impact on cell functions by lncRNAs and circRNAs regulating AKT and its effectors is poorly understood. This review provides comprehensive information about the relationship of lncRNAs and circRNAs with AKT on the cell functions of cancer cells. the roles of several lncRNAs and circRNAs acting on AKT effectors, such as FOXO, mTORC1/2, S6K1/2, 4EBP1, SREBP, and HIF are explored. To further validate the relationship between AKT, AKT effectors, lncRNAs, and circRNAs, more predicted AKT- and AKT effector-targeting lncRNAs and circRNAs were retrieved from the LncTarD and circBase databases. Consistently, using an in-depth literature survey, these AKT- and AKT effector-targeting database lncRNAs and circRNAs were related to cell functions. Therefore, some lncRNAs and circRNAs can regulate several cell functions through modulating AKT and AKT effectors. This review provides insights into a comprehensive network of AKT and AKT effectors connecting to lncRNAs and circRNAs in the regulation of cancer cell functions.

Accordingly, different lncRNAs may promote or suppress apoptosis by phosphorylating or dephosphorylating AKT to regulate its activity. As mentioned above, some tumors are overexpressed or downregulated by AKT-regulating lncRNAs. A strategy to overexpress or downregulate these specific AKT-regulating lncRNAs can improve the apoptosis-inducible effects for cancer treatment.

ER Stress by AKT-Regulating LncRNAs
Drug-induced ER stress effects of lncRNA involving AKT have been reported. 5-Fluorouracil induces ER stress and glucose-regulated protein 78 (GRP78; BiP) expression of breast cancer cells to cause 5-fluorouracil resistance, accompanied by upregulating myocardial infarction-associated transcript (MIAT lncRNA) and AKT protein expression [52]. This warrants surveying more lncRNAs that regulate other ER stress components in the future.

DNA Damage Response by AKT-Regulating LncRNAs
DNA repair-suppressing effects of lncRNAs involving AKT have been reported. Linc00312 directly targets the DNA-dependent protein kinase, catalytic subunit (DNA-PKcs), blocks the interaction between DNA-PKcs and Ku80, and inactivates AKT by dephosphorylation, suppressing nonhomologous end joining (NHEJ) repair in nasopharyngeal cancer cells [53]. This warrants surveying more lncRNAs that regulate other DNA damage and repair in the future.

Senescence by AKT-Regulating LncRNAs
Senescence-inducible effects of lncRNAs involving AKT have been reported. GAS5 silencing induces proliferation and suppresses the senescence of endothelial progenitor cells by dephosphorylating PI3K/AKT [54]. This warrants a detailed survey and examination of senescence effects of AKT-targeting lncRNAs on cancer cells in the future.
In contrast, some lncRNA studies investigated migration-suppressing effects. Plateletderived growth factor BB (PDGF-BB) inhibits RP5-857K21.7 expression of airway smooth muscle cells (ASMCs). RP5-857K21.7 overexpression inhibits the migration of PDGF-BBtreated ASMCs through dephosphorylating AKT [60]. Accordingly, different lncRNAs may promote or suppress migration by phosphorylating or dephosphorylating AKT. This warrants a detailed survey and examination of migration effects of AKT-targeting lncRNAs on cancer cells in the future.

Potential Future Directions
As described above, several lncRNAs were mentioned to regulate AKT phosphorylation or dephosphorylation for its activation and inactivation and, in turn, control cell functions. Some AKT-regulating lncRNAs are abundant or scarce in various cancers. Overexpressing or downregulating these AKT-regulating lncRNAs may reverse the status of cancer cell functions to improve anticancer effects.
However, the cell function mechanism for the modulating effects of lncRNAs on AKT remains unclear, particularly for assessing the potential targeting to AKT by lncRNAs. More experiments are warranted to improve the connection between AKT-lncRNAs regulating cancer cell functions.

Connecting AKT1/AKT2/AKT3 and Database-LncRNAs to Cell Functions
To further validate the relationship between AKT and lncRNAs to cell functions, more potential AKT-targeting lncRNAs are required. By choosing lncRNA databases, such as LncTarD [38], more AKT-targeting lncRNA candidates are generated. LncTarD is a comprehensive lncRNA database, including disease-associated lncRNA-target regulations with experiment supports, associations, and targets to biological functions, as well as TCGA pan-cancer data. By individual input target genes such as "AKT1, AKT2, and AKT3," their respective predicted lncRNAs are generated and exported. LncTarD also provides the evidence description for each predicted lncRNA. However, these LncTarDpredicted lncRNAs for AKT1, AKT2, and AKT3 did not provide potential cell functions. Subsequently, these candidates were used for a literature survey (Google Scholar and PubMed) to check their possible cell functions. Finally, the connection between these AKT-targeting database lncRNA candidates and cell functions was established ( Figure 2).

Figure 2.
Strategy for connecting database-predicted AKT-, AKT effector-targeting lncRNAs and circRNAs to their regulating cell functions. By searching LncTarD [38] and circBase [61], these AKTand AKT effector-targeting lncRNA and circRNA candidates were retrieved by individual input of gene names for AKT1, AKT2, and AKT3, as well as AKT effectors. Subsequently, they were applied to a literature survey by Google Scholar and PubMed to check their potential cell functions.
Interestingly, the lncRNA targets for AKT1, AKT2, and AKT3 are not overlapping. Notably, the investigation of AKTs should be concerned with transcriptional regulation regarding their respective lncRNAs. The relationship between AKT1, AKT2, and AKT3 connecting to database lncRNAs in regulating cell functions will be explored further below.
2.2.1. AKT1-, AKT2-, and AKT3-Targeting Database LncRNAs and Cell Functions Although the respective AKT1-, AKT2-, and AKT3-targeting lncRNAs have been reported before (Table 1), the cell functions were not connected to these AKT1-, AKT2-, and AKT3-targeting database lncRNAs. Here, we summarize and integrate available information from our in-depth literature search on Google Scholar and PubMed ( Figure 2) and . Strategy for connecting database-predicted AKT-, AKT effector-targeting lncRNAs and circRNAs to their regulating cell functions. By searching LncTarD [38] and circBase [61], these AKTand AKT effector-targeting lncRNA and circRNA candidates were retrieved by individual input of gene names for AKT1, AKT2, and AKT3, as well as AKT effectors. Subsequently, they were applied to a literature survey by Google Scholar and PubMed to check their potential cell functions. Table 1. AKT1-, AKT2-, AKT3-targeting database lncRNAs.
Interestingly, the lncRNA targets for AKT1, AKT2, and AKT3 are not overlapping. Notably, the investigation of AKTs should be concerned with transcriptional regulation regarding their respective lncRNAs. The relationship between AKT1, AKT2, and AKT3 connecting to database lncRNAs in regulating cell functions will be explored further below.

AKT1-, AKT2-, and AKT3-Targeting Database LncRNAs and Cell Functions
Although the respective AKT1-, AKT2-, and AKT3-targeting lncRNAs have been reported before (Table 1), the cell functions were not connected to these AKT1-, AKT2-, and AKT3-targeting database lncRNAs. Here, we summarize and integrate available information from our in-depth literature search on Google Scholar and PubMed ( Figure 2) and provide novel information about the networking of the AKT1-, AKT2-, and AKT3-targeting lncRNAs and cell functions. Twelve AKT-targeting database lncRNAs are connected to cell functions, as summarized, especially for cancer cells (Table 2). Literature could not be found on Google Scholar or PubMed (12 June 2022). The lncRNAs targeting several AKT effectors were retrieved from the LncTarD database [38] (accessed on 13 June 2022).
(1) AKT1-Targeting ENST00113 and Cell Functions LncRNA ENST00113 modulating cell functions are summarized in Table 2). LncRNA ENST00113 enhances atherosclerosis development [62]. ENST00113 enhances proliferation and migration, but inhibits apoptosis of human umbilical vein endothelial cells by phosphorylating PI3K/AKT/mTOR [62]. AKT inactivation by inhibitor or siRNA suppresses atherosclerosis by upregulating the autophagy of macrophages [63]. Accordingly, this warrants a detailed assessment of the impact of ENST00113 on modulating autophagy and careful examination of cell functions due to ENST00113 on cancer cells in the future.
(2) AKT1-Targeting MALAT1 and Cell Functions MALAT1 modulating cell functions are summarized in Table 2. MALAT1 enhances the proliferation and autophagy of glioma cells [65]. MALAT1 inhibition suppresses oxygenglucose deprivation/reoxygenation-triggered apoptosis, and ER stress [66]. Upregulation of mitochondrial fusion protein mitofusin 1 (MFN1) reverses microvascular dysfunction and cardiac microvascular endothelial cell damage enhanced by MALAT1 knockdown by suppressing mitochondrial fission and apoptosis [64]. MALAT1 enhances proliferation and suppresses the senescence of gallbladder cancer cells [67]. MALAT1 improves the proliferation and migration of colon cancer cells [68]. This deserves a careful examination of cell functions due to MALAT1 to provide more evidence for impacts on cancer cells in the future.
(3) AKT1-Targeting GAS5 and Cell Functions LncRNA GAS5 modulating cell functions are summarized in Table 2. GAS5 upregulation inhibits proliferation and promotes apoptosis of pituitary neuroendocrine [69] and liver [70] cancer cells. GAS5 induces autophagy of colon [71] and breast [72] cancer cells. GAS5 blocks high glucose-induced ER stress and apoptosis of retinal epithelial cells [73]. GAS5 pathways impact ferroptosis-associated gene expressions in heart-failure tissue [74]. GAS5 knockdown increases cell viability in the hypoxia-reoxygenation model by reducing the expression of necrosis markers, such as lactate dehydrogenase [75]. GAS5 upregulation suppresses DNA repair to ionizing radiation [76]. GAS5 overexpression blocks the senescence of vascular smooth muscle cells [77]. GAS5 upregulation blocks propofol-induced migration of glioma cells [78]. Accordingly, some cell functions of GAS5 were not investi- (4) AKT1-Targeting CDKN2B-AS1 and Cell Functions CDKN2B-AS1 modulating cell functions are summarized in Table 2. CDKN2B-AS1 inhibits apoptosis and senescence of cervical cancer, which can be reverted by CDKN2B-AS1 silencing [79]. CDKN2B-AS1 upregulation induces autophagy of idiopathic pulmonary fibrosis [80]. Additionally, stress-associated endoplasmic reticulum protein 1 (SERP1) downregulates CDKN2B-AS1 and ER stress of oxygen deprivation-induced injury in cardiomyocytes [81]. CDKN2B-AS1 modifies senescence and apoptosis, involving cell cycle disturbance and DNA damage [82]. CDKN2B-AS1 improves the proliferation and metastasis of liver cancer cells [83]. Careful examination of cell functions and CDKN2B-AS1 is needed to provide more evidence for impacts on cancer cells in the future.  Table 2. HULC suppresses apoptosis of osteosarcoma [84] and lung cancer cells [85]. HULC induces autophagy of liver cancer cells [86]. HULC enhances the DNA repair of liver cancer stem cells [87]. Additionally, hepatitis B virus X protein upregulates HULC and downregulates senescence protein p18 expressions, suggesting that HULC can modulate cellular senescence [88]. HULC enhances the migration of pancreatic [89] and liver [90] cancer cells. This warrants a detailed examination of cell functions influenced by HULC to provide more evidence for their impacts on cancer cells in the future.  Table 2. LUCAT1 overexpression induces autophagy and metastasis, but suppresses apoptosis of lung cancer cells and promotes its cisplatin resistance [91]. LUCAT1 is reported to be the ferroptosisrelated lncRNA correlated with renal cancer survival [92]. LUCAT1 is reported to be the necroptosis-related lncRNA in liver tumors [93]. LUCAT1 suppresses DNA damage and apoptosis of colon cancer cells [94]. A detailed examination of cell functions and LUCAT1 is warranted to provide more evidence for their impacts on cancer cells in the future.  Table 2. RP11-708H21.4 has low expression in colon cancer cells. RP11-708H21.4 overexpression decreases proliferation and migration and triggers apoptosis of colon cancer cells by dephosphorylating AKT and mTOR [95]. Additionally, AFAP1-AS1 silencing decreases proliferation and migration and induces apoptosis of lung cancer cells [96]. LINC00462 silencing suppresses high glucose-triggered apoptosis of renal tubular epithelial cells [97]. LINC00462 improves the invasion of pancreatic cancer cells [98]. A detailed assessment of cell functions influenced by RP11-708H21.4, AFAP1-AS1, and LINC00462 is warranted to provide more evidence for their impacts on cancer cells in the future.  Table 2. LOXL1-AS1 suppresses proliferation and migration and enhances apoptosis of breast cancer cells [99]. The lncRNA FOXD2-AS1 knockdown decreases proliferation and migration but triggers apoptosis of glioma cells [100]. AB073614 enhances proliferation and triggers apoptosis of cervical cancer cells [101]. AB073614 improves metastasis of gastric cancer cells [102]. This warrants a detailed assessment of cell functions influenced by LOXL1-AS1, FOXD2-AS1, and AB073614 to provide more evidence for their impacts on cancer cells in the future.  Table 2. H19 silencing blocks proliferation and triggers apoptosis of vascular smooth muscle cells [103]. H19 upregulation enhances invasion and autophagy of trophoblast cells [104]. H19 knockdown promotes resveratrol-induced ER stress and necroptosis of gastric cancer cells by increasing GRP78, receptor-interacting serine/threonine-protein kinase 1 (RIPK1), and mixed lineage kinase domain-like (MLKL) expressions [105]. H19 silencing enhances the ferroptosis of lung cancer cells [107]. Additionally, lncRNA H19 downregulates mitochondrial fusion expression of the MFN2 gene in renal tissues of diabetic rats [106]. H19 silencing suppresses ionizing radiation-induced DNA damage of lung cancer cells, but enhances DNA repair [108]. H19 triggers the senescence of cardiomyocytes [109]. Accordingly, some cell functions of H19 have not been investigated in cancer cells. Careful examination of some cell functions influenced by H19 is needed to provide more evidence for their impacts on cancer cells in the future.  Table 2. SPRY4-IT1 downregulation improves apoptosis of pancreatic cancer cells [110]. SPRY4-IT1-expressing primary human melanocytes show gene expression changes along with apoptosis and DNA damage responses [111]. SPRY4-IT1 enhances metastasis in nasopharyngeal cancer cells [112]. LINC00312 suppresses proliferation and triggers apoptosis of lung cancer cells [113]. LINC00312 suppresses DNA repair of nasopharyngeal cancer cells by targeting DNA-PKcs [53]. LINC00312 suppresses the migration of bladder cancer cells [114]. A detailed assessment of cell functions influenced by SPRY4-IT1 and LINC00312 is warranted to provide more evidence for their impacts on cancer cells in the future.  Table 2. For AKT2, lncRNA-p3134 upregulation suppresses the β-cell apoptosis of pancreatic β-cells [115]. According to our literature survey, other cell functions related to AKT2 have not been reported.
(12) AKT3-Targeting FEZF1-AS1 and Cell Functions FEZF1-AS1 modulating cell functions are summarized in Table 2. For AKT3, FEZF1-AS1 exhibits higher expression in ovarian cancer tissues and cells than normal controls [116]. Ovarian cancer patients with high FEZF1-AS1 show a poor prognosis. FEZF1-AS1 silencing inhibits proliferation and induces apoptosis of ovarian cancer cells [116]. Similarly, FEZF1-AS1 is overexpressed in gastric tumors. FEZF1-AS1 overexpression improves proliferation and autophagy of gastric cancer cells, reverted by ATG5 silencing [117]. A detailed assessment of cell functions influenced by FEZF1-AS1 is warranted to provide more evidence for their impacts on cancer cells in the future.

Potential Future Directions
As described above, a literature survey connected AKT1-, AKT2-, and AKT3-targeting database lncRNAs to several cell functions. However, most information was derived from AKT1 in our survey ( Table 2). AKT2 and AKT3 were rarely investigated. This warrants a detailed assessment of the role of AKT2 and AKT3 targeting by lncRNAs in regulating cancer cell functions in the future. Some lncRNAs reported in some cell functions but not others are based on a literature survey. Their possible contributions to unreported cell functions are not excluded and need further inspection.

AKT Effector (FOXO)-Regulating LncRNAs and Cell Functions
The relationship between FOXO, lncRNA, and cell functions such as autophagy, ER stress, necroptosis, DNA damage response, and senescence were rarely reported. Other functions, such as apoptosis, ferroptosis, and migration were mentioned, as follows (Table 3).

(1) Apoptosis by FOXO-Regulating LncRNAs
Several lncRNA studies investigated apoptosis modulating effects involving FOXO (Table 3). Under energy stress, FOXO upregulates FOXO-induced lncRNA 1 (FILNC1) to suppress proliferation and induce apoptosis of renal cancer cells [118]. siRNA may induce or suppress apoptosis involving FOXO. In contrast, LINC00899 silencing downregulates FOXO expression and induces apoptosis of spinal ependymoma cells [119]. A detailed assessment of apoptosis influenced by more FOXO-regulating lncRNAs is warranted to provide more evidence for their impacts on cancer cells in the future.

(3) Migration by FOXO-Regulating LncRNAs
Several lncRNA studies investigated migration-modulating effects involving FOXO (Table 3). LINC00899 knockdown inhibits FOXO expression and migration of spinal ependymoma cells [119]. Oncogene E26 transformation-specific or E-twenty-six (ETS)-related gene (ERG), an oncogenic transcription factor, upregulates LINC00920 to promote the proliferation and migration of prostate cancer cells by downregulating FOXO expression [121]. A detailed assessment of migration influenced by more FOXO-regulating lncRNAs is warranted to provide more evidence for their impacts on cancer cells in the future.

AKT Effector (c-Myc)-Regulating LncRNAs and Cell Functions
There is little information about the relationship between c-Myc, lncRNA, and cell functions, such as mitochondrial morphogenesis. Other functions, such as apoptosis, autophagy, ER stress, ferroptosis, necroptosis, DNA damage response, senescence, and migration were mentioned as follows (Table 3).
(1) Apoptosis by c-Myc-Regulating LncRNAs Several lncRNA studies investigated apoptosis-modulating effects involving c-Myc (Table 3). In some cases, lncRNAs may regulate c-Myc by direct targeting. Lnc-EPIC1 silencing triggers apoptosis of colon cancer cells by directly binding to c-Myc and downregulating c-Myc downstream effectors [122]. However, most of the c-Myc-regulating lncRNAs did not investigate their targeting potential. Inhibition of lncRNA MIR22HG suppresses proliferation and induces apoptosis of esophageal cancer cells via downregulating c-Myc expression [123]. LncRNA KCNQ1OT1 silencing causes apoptosis of acute myeloid leukemia by decreasing c-Myc expression [124]. LINC01503 is downregulated by c-Myc silencing to induce apoptosis of lung cancer cells [125], suggesting that c-Myc may upregulate LINC01503 to inhibit the apoptosis of lung cancer cells [125]. A detailed assessment of apoptosis influenced by more c-Myc-regulating lncRNAs is warranted to provide more evidence for their impacts on cancer cells in the future.

(3) ER Stress by c-Myc-Regulating LncRNAs
Several lncRNA studies investigated ER stress-modulating effects involving c-Myc (Table 3). c-Myc improves adaptive ER stress [129]. Metformin upregulates the expressions of lncRNA MALAT1 and ER stress genes, while MALAT1 knockdown in metformin-treated breast cancer cells shows reduced phosphorylation of c-Myc [130]. Accordingly, MALAT1 is a potential upstream regulator to c-Myc for triggering ER stress. IA detailed assessment of ER stress influenced by more c-Myc-regulating lncRNAs is warranted to provide more evidence for their impacts on cancer cells in the future.

(4) Ferroptosis by c-Myc-Regulating LncRNAs
Ferroptosis-modulating effects of lncRNAs involving c-Myc were reported (Table 3). Transcription factor AP-2 gamma (TFAP2C) transcriptionally activates lncRNA PCAT1 to suppress ferroptosis of prostate cancer cells by interacting with c-Myc [131]. A detailed assessment of ferroptosis influenced by more c-Myc-regulating lncRNAs is warranted to provide more evidence for their impacts on cancer cells in the future.  (Table 3). Linc00176 is highly expressed in liver cancer cells, which is activated by c-Myc. Linc00176 knockdown promotes necroptosis of liver cancer cells [132]. Accordingly, c-Myc may modulate linc00176 expression to control necroptosis. A detailed assessment of necroptosis influenced by more c-Myc-regulating lncRNAs is warranted to provide more evidence for their impacts on cancer cells in the future.  (Table 3). LncRNA may induce or suppress DNA repair connecting to c-Myc. LncRNA PVT1 improves DNA repair and suppresses cell apoptosis of nasopharyngeal cancer cells [133]. p53 activates PVT1b to reduce c-Myc transcription and suppress carcinogenesis [134]. A detailed investigation of the interaction between PVT1b and Myc in modulating DNA repair is particularly needed here. Similarly, noncoding RNA activated by DNA damage (NORAD) knockdown in neuroblastoma cells upregulates the poly [ADPribose] polymerase 1 (PARP1), a DNA damage sensor for DNA repair [135]. In contrast, in gene set enrichment analysis (GSEA), head neck cancer patients with low lncRNA NEAT1 expression exhibit upregulation of c-Myc and DNA repair signaling [136]. A detailed assessment of DNA damage response influenced by more c-Myc-regulating lncRNAs is warranted to provide more evidence for their impacts on cancer cells in the future. Several lncRNA studies investigated senescence-modulating effects involving c-Myc (Table 3). Several lncRNA studies reported senescence-suppressing results connecting to c-Myc. LncRNA PARROT, an upstream modulator of c-Myc, is downregulated in the senescence of human mammary epithelial cells [137]. c-Myc may transcriptionally activate some lncRNAs, such as USP2-AS1, to inhibit senescence and improve the proliferation of lung cancer cells [138]. C1RL-AS1 knockdown promotes the senescence of gastric cancer cells by decreasing c-Myc expression [139]. c-Myc upregulates ovarian adenocarcinoma-amplified lncRNA (OVAAL) transcription to promote tumor growth and inhibit senescence [140]. A detailed assessment of senescence influenced by more c-Myc-regulating lncRNAs is warranted to provide more evidence for their impacts on cancer cells in the future.

(8) Migration by c-Myc-Regulating LncRNAs
Several lncRNA studies investigated migration-modulating effects involving c-Myc (Table 3). Several lncRNA studies reported migration-promoting results connecting to c-Myc. LINC00665 promotes c-Myc transcriptional activity to enhance the migration of lung cancer cells [141]. LncRNA AFAP1-AS1 [142] and MIR210HG [143] strengthen the migration of lung and gastric cancer cells by upregulating c-Myc, respectively. c-Myc can bind to the LINC01050 promoter to improve transcription of LINC01050 and enhances metastasis of gastric cancer cells [144]. A detailed assessment of migration influenced by more c-Myc-regulating lncRNAs is warranted to provide more evidence for their impacts on cancer cells in the future.

AKT Effector (mTORC1)-Regulating LncRNAs and Cell Functions
There is little information about the relationship between mTORC1, lncRNA, and cell functions. Other functions, such as apoptosis, autophagy, and migration, were mentioned as follows (Table 3).

(1) Apoptosis by mTORC1-Regulating LncRNAs
There are studies on apoptosis modulating the effects of lncRNA involving mTORC1 (Table 3). LncRNA H19 suppresses mTORC1 expression of pituitary tumors [145]. Additionally, the apoptosis-promoting effects of lncRNA were reported. LINC00998 enhances mTORC2 decay and apoptosis to suppress carcinogenesis, reverted by mTORC2 overexpression [146]. A detailed assessment of apoptosis influenced by more mTORC1-regulating lncRNAs is warranted to provide more evidence for their impacts on cancer cells in the future.
(2) Autophagy by mTORC1-Regulating LncRNAs Several lncRNA studies investigated autophagy-modulating effects involving mTORC1 (Table 3). Autophagy-inducing or -suppressing lncRNAs connecting to mTORC1 were reported. LncRNA ZNNT1 promotes autophagy of uveal melanoma cells by mTORC1 inhibitor [147]. In contrast, HAGLR opposite strand lncRNA (HAGLROS) binds to mTORC1 components and activates mTORC1 signaling by mTOR phosphorylation to inhibit autophagy, contributing to gastric carcinogenesis [148]. A detailed assessment of autophagy influenced by more mTORC1-regulating lncRNAs is warranted to provide more evidence for their impacts on cancer cells in the future.
(3) Senescence by mTORC1-Regulating LncRNAs Senescence-modulating effects of lncRNAs involving mTORC1 were reported (Table 3). Senescence-promoting effects of lncRNA connecting to mTORC1 were demonstrated. In non-TGF-β-treated cells, silencing of the metastasis-associated in lung adenocarcinoma transcript 1 (MALAT1) activates mTORC1 [149], associated with cell senescence in chronic obstructive pulmonary disease (COPD). Accordingly, the senescence effects of mTORC1regulating lncRNAs were not well investigated in cancer cells. A careful examination for senescence influenced by mTORC1-regulating lncRNAs on cancer cells is warranted.

(4) Migration by mTORC1-Regulating LncRNAs
Several lncRNA studies investigated migration-modulating effects involving mTORC1 (Table 3). In particular, migration-promoting effects of lncRNA connecting to mTORC1 were reported. RHPN1-AS1 silencing blocks the migration of nasopharyngeal cancer cells by decreasing MMP 2/9 expression [150]. LINC00958 activates the mTORC1 to promote the epithelial-mesenchymal transition (EMT) and migration of liver cancer cells [151]. A detailed assessment of migration influenced by more mTORC1-regulating lncRNAs is warranted to provide more evidence for their impacts on cancer cells in the future.

AKT Effector (SREBP1)-Regulating LncRNAs and Cell Functions
As mentioned above, the relationship between SREBP1, lncRNA, and cell functions was rarely reported. Other functions, such as apoptosis and autophagy, were mentioned as follows (Table 3).
(2) Autophagy by SREBP1-Regulating LncRNAs Autophagy-modulating effects of lncRNAs involving SREBP1 were reported (Table 3). HAGLROS knockdown downregulates SREBP1 and induces autophagy to reduce intrahepatic cholangiocarcinoma cell proliferation [154]. A detailed assessment of autophagy influenced by more SREBP1-regulating lncRNAs is warranted to provide more evidence for their impacts on cancer cells in the future.

AKT Effector (HIF)-Regulating LncRNAs and Cell Functions
The role of HIF in regulating lncRNA-associated ER stress, necroptosis, DNA damage response, and senescence was rarely reported. Other functions involving HIF and lncRNA are summarized in Table 3.
In contrast, JPX overexpression inhibits apoptosis of nucleus pulposus cells by upregulating HIF1A [158]. Similarly, UCA1 overexpression blocks apoptosis of breast cancer cells by HIF1A inhibitor [159]. A detailed assessment of apoptosis influenced by more HIF-regulating lncRNAs is warranted to provide more evidence for their impacts on cancer cells in the future.
(2) Autophagy by HIF-Regulating LncRNAs Several lncRNA studies reported autophagy-modulating effects involving HIF ( Table 3). The autophagy-promoting effects of lncRNA connecting to HIF were reported. Hypoxia upregulates lncRNA-MALAT1 and induces autophagy of endometrial stromal cells by upregulating HIF1A expression [160]. Hypoxia upregulates MALAT1 to trigger autophagy of vascular endothelial cell injury by downregulating HIF1A [161]. PVT1 lncRNA knockdown suppresses autophagy by downregulating HIF1A in pancreatic cancer cells [162]. A detailed assessment of autophagy influenced by more HIF-regulating lncRNAs is warranted to provide more evidence for their impacts on cancer cells in the future.

(3) Ferroptosis by HIF-Regulating LncRNAs
Ferroptosis-modulating effects of lncRNAs involving HIF were reported ( Table 3). The ferroptosis-suppressing effects of lncRNA connecting to HIF were reported. Hypoxiaupregulated HIF1A/lncRNA-PMAN suppressed ferroptosis of gastric cancer cells [163]. A detailed assessment of ferroptosis influenced by more HIF-regulating lncRNAs is warranted to provide more evidence for their impacts on cancer cells in the future.
(4) DNA Damage Response by HIF-Regulating LncRNAs DNA repair-modulating effects of lncRNA involving HIF were reported ( Table 3). The DNA repair-suppressing effects of lncRNA connecting to HIF were reported. LncRNA HITT (HIF1A inhibitor at translation level) directly interacts with ataxia-telangiectasia mutated (ATM) and suppresses homologous recombination repair in human colon cancer tissues [164]. A detailed assessment of DNA damage response influenced by more HIFregulating lncRNAs is warranted to provide more evidence for their impacts on cancer cells in the future.

(5) Migration by HIF-Regulating LncRNAs
Several lncRNA studies investigated migration-modulating effects involving HIF ( Table 3). The migration-promoting and -suppressing effects of lncRNA connecting to HIF were reported. HIF1A and HIF-2α can transcriptionally activate hypoxia-responsive lncRNA MALAT1 to enhance the migration of breast cancer cells [165]. LncRNA ZFPM2-AS1 enhances the migration of liver cancer cells by upregulating HIF1A [166]. LINC00649 enhances metastasis of breast cancer cells by increasing HIF1A stability [167]. LncRNA MIR17HG improves the migration of retinoblastoma cells by increasing HIF1A expression [168]. HIF1A upregulates TM4SF1-AS1 expression to enhance the migration of liver cancer cells [169]. LncRNA FAM83A-AS1 enhances the migration of lung cancer cells by upregulating HIF1A [170]. In contrast, lncRNA TSLNC8 suppresses migration effects on lung cancer cells by regulating HIF1A signaling [155]. A detailed assessment of migration influenced by more HIF-regulating lncRNAs is warranted to provide more evidence for their impacts on cancer cells in the future.
2.3.6. Potential Future Directions As described above, several lncRNAs were mentioned to regulate AKT effectors and, in turn, control cell functions. Overexpressing or downregulating these AKT effectorregulating lncRNAs may reverse the status of cancer cell functions to improve the anticancer effects. However, the cell function mechanism for the modulating impact of lncRNAs on AKT effectors remains unclear, particularly for assessing the potential targeting to AKT effectors by lncRNAs. More experiments are warranted to improve understanding of the connection between AKT effectors and lncRNAs regulating cancer cell functions.

Connecting AKT Effectors and Database LncRNAs to Cell Functions
To further validate the relationship of AKT effectors and lncRNAs to cell functions, more AKT effector-targeting lncRNAs are required. By choosing an lncRNA database such as the LncTarD database [38], more AKT effector-targeting lncRNA candidates are generated. By individual input target genes such as "FOXO, c-Myc, mTOR, RPTOR, MLST8, AKT1S1, DEPTOR, RPS6KB1, RPS6KB2, 4EBP1, SREBF1, and HIF1A," their respective predicted lncRNAs are generated and exported. However, these LncTarD-predicted lncRNAs for AKT effectors did not provide potential cell functions. Subsequently, these candidates were used for literature searches (Google Scholar and PubMed) to establish the connection between AKT effector-targeting lncRNAs and cell functions (Figure 2).
Interestingly, most AKT effector-targeting lncRNAs do not overlap, but some AKT effector-targeting lncRNAs overlap. The latter holds for PVT1, which can target the AKT effectors c-Myc and mTOR (Tables 4 and 5). HOTAIR can target the AKT effectors (mTOR, S6K1, and HIF1A). Additionally, some lncRNAs may provide dual functions for different cancer cells. For example, HOTAIR is upregulated in cervical cancer cells but downregulated in oral cancer cells [38]. UCA1 is upregulated in bladder cancer cells but downregulated in colon cancer cells. Although the respective lncRNAs of these AKT effectors were reported, the cell functions were not connected to these AKT effector-associated lncRNAs. FOXO, mTORC1 complex (including RPTOR, MLST8, AKT1S1, and DEPTOR), S6K2, and 4EBP1 targeted by lncRNAs were omitted because they were not available after the retrieval of the LncTarD database [38] (13 June 2022). mTOR is one of the components of mTORC1. Literature could not be found by searching Google Scholar and PubMed (12 June 2022).

AKT Effector (c-Myc)-Targeting LncRNAs and Cell Functions
Several c-Myc-targeting lncRNAs and their respective cell functions (Table 5) were mentioned in detail, as follows.
(1) c-Myc-Targeting PVT1 and Cell Functions PVT1 modulating cell functions are summarized in Table 5. PVT1 inhibits apoptosis of colon [171] and thyroid [172] cancer cells. PVT1 promotes the autophagy of liver cancer cells [173]. PVT1 upregulation suppresses inflammation-induced mitochondrial fission and enhances mitochondrial fusion of myoblasts [252]. PVT1 downregulation promotes the ferroptosis of live cancer cells [174]. Additionally, PVT1 was reported as a necroptosisassociated lncRNA of gastric cancer [175]. PVT1b, the p53-dependent PVT1 isoform, is a modulator of senescence [176]. PVT1 silencing triggers apoptosis and suppresses the radioresistance of nasopharyngeal cancer cells by inhibiting DNA repair [133]. PVT1 promotes the invasion of bladder cancer cells [177]. A careful examination of some cell functions influenced by c-Myc-targeting PVT1 is warranted to provide more evidence for their impacts on cancer cells in the future.
(2) c-Myc-Targeting HOTTIP and Cell Functions HOTTIP modulating cell functions are summarized in Table 5. HOTTIP silencing triggers apoptosis of human retinoblastoma cells, while HOTTIP overexpression suppresses apoptosis [178]. HOTTIP knockdown suppresses proliferation and migration but causes autophagy of renal cancer cells, reverted by autophagy inhibitor [179]. HOTTIP promotes DNA repair of UV-irradiated spermatogenic cells by upregulating γH2AX and p53 expression [180]. HOTTIP is involved in regulating senescence [181]. HOTTIP enhances the proliferation and migration of osteosarcoma cells [182]. A careful examination of some cell functions influenced by c-Myc-targeting HOTTIP is warranted to provide more evidence for their impacts on cancer cells in the future.  Table 5. CRNDE knockdown enhances apoptosis of colon cancer cells [183]. CRNDE enhances ATG4B-dependent autophagy of liver cancer cells [184]. Additionally, CRNDE silencing suppresses ER stress and the migration of endothelial cells [185]. Inhibition of CRNDE with oxaliplatin treatment enhances DNA damage and apoptosis of colon cancer cells, reverted by upregulating CRNDE with OXA oxaliplatin [186]. A careful examination of some cell functions influenced by c-Myc-targeting CRNDE is warranted to provide more evidence for their impacts on cancer cells in the future.
(4) c-Myc-Targeting CCAT2 and HNF1A-AS1 and Cell Functions CCAT2 and HNF1A-AS1 modulating cell functions are summarized in Table 5. CCAT2 inhibits apoptosis of colorectal cancer cells [187]. CCAT2 induces autophagy and migration of liver cancer cells [188]. HNF1A-AS1 inhibits apoptosis of bladder cancer cells [189]. HNF1A-AS1 promotes the autophagy of liver cancer cells [190]. HNF1A-AS1 enhances the invasion of lung cancer cells [191]. A careful examination of some cell functions influenced by c-Myc-targeting CCAT2 and HNF1A-AS1 is warranted to provide more evidence for their impacts on cancer cells in the future.  Table 5. PCAT1 knockdown triggers apoptosis of head and neck cancer cells [192]. Transcription factor AP-2 gamma (TFAP2C)-dependent PCAT1 suppresses ferroptosis of prostate cancer cells [131]. PCAT1 silencing promotes radiation-induced DNA damage [193]. PCAT1 improves the migration of laryngeal cancer cells [194]. A careful examination of some cell functions influenced by c-Myc-targeting PCAT1 is warranted to provide more evidence for their impacts on cancer cells in the future.  Table 5. SNHG1 silencing triggers apoptosis and blocks the migration of liver cancer cells [195]. SNHG1 induces autophagy and invasion of bladder cancer cells [196]. Downregulation of nonsense-mediated mRNA decay (NMD) effectors (SMG1 and SMG7) upregulate SNHG1 gene expression during ER stress [197]. lncRNA-BCAT1 upregulation decreases the proliferation and invasion of colon cancer cells [198]. A careful examination of some cell functions influenced by c-Myc-targeting SNHG1 and lncRNA-BCAT1 is warranted to provide more evidence for their impacts on cancer cells in the future.  Table 5. NEAT1 inhibits proliferation and migration and induces apoptosis of cervical cancer cells [199]. NEAT1 promotes autophagy of liver cancer cells to induce radioresistance [253]. NEAT1 overexpression inhibits ER stress and migration and promotes apoptosis in gastric cancer cells [200]. Additionally, NEAT1 blocks the homologous recombination of the DNA repair pathway to inhibit the proliferation of multiple myeloma [202]. NEAT1 inhibits the doxorubicin-triggered senescence of cardiomyocytes [203]. Exosome-derived NEAT1 enhances ferroptosis to promote sepsis-induced encephalopathy [201]. A careful examination of some cell functions influenced by c-Myc-targeting NEAT1 is warranted to provide more evidence for their impacts on cancer cells in the future.  Table 5. CERNA2 downregulation suppresses proliferation and triggers apoptosis of gastric cancer cells [204]. CERNA2 silencing suppresses the migration of cervical cancer cells [205]. PCAT6 suppresses apoptosis of colon cancer cells [206]. Additionally, PCAT6 induces autophagy and improves the malignancy of colon cancer cells [207]. PCAT6 was reported to be a ferroptosis-associated lncRNA for diagnosing liver cancer cells [208]. High PCAT6 levels were linked to the worse overall survival of colon cancer, accompanied by changing base excision repair and senescence [209]. PCAT6 silencing blocks the proliferation and invasion of lung cancer cells [210]. A careful examination of some cell functions influenced by c-Myc-targeting CERNA2 and PCAT6 is warranted to provide more evidence for their impacts on cancer cells in the future.  Table 5. TUG1 suppresses apoptosis of cervical cancer cells [211]. TUG1 suppresses ER stress and apoptosis of renal tubular epithelial cells [213]. TUG1 inhibits ferroptosis of hypoxia/reoxygenation treated proximal tubular epithelial cells [214]. Additionally, TUG1 silencing suppresses bupivacaine-induced DNA damage for neurotoxicity [215]. TUG1 upregulation improves the senescence of lung cancer cells [216]. TUG1 improves the autophagy of colorectal cancer cells to enhance cisplatin resistance [212]. TUG1 enhances the proliferation and invasion of osteosarcoma cells [217]. A careful examination of some cell functions influenced by c-Myc-targeting TUG1 is warranted to provide more evidence for their impacts on cancer cells in the future.  Table 5. Breast cancer cells highly express LINC-ROR, suppressing gemcitabine-induced autophagy and apoptosis [218]. Arsenite enhances LINC-ROR expression involved in DNA repair [219]. LINC-ROR enhances the migration of pancreatic cancer cells [220]. FILNC1 knockdown suppresses apoptosis of renal cancer cells [118]. A careful examination of some cell functions influenced by c-Myc-targeting LINC-ROR and FILNC1 is warranted to provide more evidence for their impacts on cancer cells in the future.

AKT Effector (mTOR)-Targeting LncRNAs and Cell Functions
Several mTOR-targeting lncRNAs and their respective cell functions (Table 5) were mentioned in detail.
(1) mTOR-Targeting HOTAIR and Cell Functions HOTAIR modulating cell functions are summarized in Table 5. Propofol suppresses HOTAIR to trigger apoptosis of cervical cancer cells [221]. HOTAIR promotes the autophagy of gastrointestinal stromal cancer cells to enhance their resistance to imatinib [222]. HOTAIR upregulation suppresses the paeonol-inhibiting ferroptosis of neuronal cells [224]. Additionally, DNA damage promotes HOTAIR expression in ovarian cancer cells. HOTAIR overexpression enhances DNA damage response [225]. HOTAIR improves interleukin 6 secretion after DNA damage associated with senescence [254]. Furthermore, HOTAIR knockdown inhibits autophagy and migration of cervical cancer cells [223]. A careful examination of some cell functions influenced by mTOR-targeting HOTAIR is warranted to provide more evidence for their impacts on cancer cells in the future.
(2) mTOR-Targeting UCA1 and Cell Functions UCA1 modulating cell functions are summarized in Table 5. Curcumin suppresses proliferation and promotes apoptosis of lung cancer cells by inhibiting UCA1 [226]. UCA1 induces autophagy of leukemia cells [227]. UCA1 inhibits ER stress to suppress ischemia/ reperfusion-triggered apoptosis of cardiomyocytes [228]. UCA1 silencing upregulates dynamin-related protein 1 (DRP1) and FIS1 expression leading to mitochondria fission of pancreatic cancer cells [229]. Additionally, UCA1 silencing promotes temozolomideinduced apoptosis and DNA damage to glioma cells [230]. Coactivators of activator protein 1 (AP1) and estrogen receptor α (CAPERα) cooperate with UCA1 to induce senescence of human foreskin fibroblasts [231]. UCA1 knockdown suppresses EMT expression and migration of pulmonary fibrosis [232]. A careful examination of some cell functions influenced by mTOR-targeting UCA1 is warranted to provide more evidence for their impacts on cancer cells in the future.

AKT Effector (SREBP1)-Targeting LncRNAs and Cell Functions
The SREBP1-targeting lncRNA LNCARSR and its respective cell functions (Table 5) were mentioned in detail. LNCARSR silencing triggers apoptosis of osteosarcoma cells [236]. LNCARSR improves the proliferation and invasion of ovarian cancer cells [237]. A careful examination of some cell functions influenced by SREBP1-targeting LNCARSR is warranted to provide more evidence for their impacts on cancer cells in the future.

AKT Effector (HIF)-Targeting LncRNAs and Cell Functions
Several HIF-targeting lncRNAs and their respective cell functions (Table 5) were mentioned in detail.
LncRNA CPS1-IT1 inhibits EMT and migration of colon cancer cells by downregulating hypoxia-induced autophagy [239]. CPS1-IT1 overexpression inhibits the proliferation and migration of glioma cells [240]. A careful examination of some cell functions influenced by HIF-targeting CPS1-IT1 is warranted to provide more evidence for their impacts on cancer cells in the future.
(2) HIF1A-Targeting MIR31HG and Cell Functions MIR31HG modulating cell functions are summarized in Table 5. MIR31HG improves proliferation and suppresses head and neck cancer cell apoptosis [241]. Additionally, MIR31HG silencing improves the senescence phenotype of fibroblasts [242]. MIR31HG silencing suppresses the migration of neuroblastoma cells [243]. A careful examination of some cell functions influenced by HIF1A-targeting MIR31HG is warranted to provide more evidence for their impacts on cancer cells in the future.  Table 5. MEG3 upregulation promotes ER stress-associated protein expressions and triggers apoptosis of esophageal cancer cells [244]. MEG3 overexpression triggers autophagy of ovarian cancer cells [245]. MEG3 silencing inhibits DRP1 expression and mitochondrial fission of podocytes, reverted by MEG3 overexpression [246]. Additionally, MEG3 silencing suppresses the ferroptosis of rat brain microvascular endothelial cells [247]. MEG3 triggers necroptosis of neuron cells [248]. MEG3 maintains endothelial function by modulating the DNA damage response [249]. MEG3 suppresses the senescence of vascular endothelial cells [250]. MEG3 decreases the proliferation and invasion of colon cancer cells [251]. A careful examination of more cell functions influenced by HIF1A-targeting MEG3 on cancer cells is warranted.
Some studies provide direct evidence that these lncRNAs may modulate AKT to regulate some AKT effectors. AKT and mTOR induce macrophage autophagy, as evidenced by their inhibitors [63]. ENST00113 silencing blocks the migration of HUVEC cells, accompanied by dephosphorylation of AKT and mTOR [62]. H19 upregulation improves AKT and mTOR phosphorylation to induce invasion and autophagy of trophoblast cells, reverted by H19 knockdown [104]. Consequently, some lncRNAs can modulate AKT and AKT effectors to regulate cell functions, as shown in Figure 1.
As described above, we provided comprehensive information for connecting AKT/AKT effectors with lncRNAs regulating cell functions. AKT1, AKT2, and AKT3 can control several AKT effectors. AKT stimulates mTORC1 through mTOR phosphorylation [255] and, in turn, suppresses 4EBP1 expression, a c-Myc negative regulator [256]. mTOR also phosphorylates and activates S6K1/2 [255] to upregulate SREBP1 expression [4]. mTOR upregulates HIF1A expression. Meanwhile, AKT inhibits FOXO expression [4,257]. However, the information for AKT-and its effector-targeting lncRNAs were arranged in different sections and tables, lacking a schematic summary. Therefore, we provide a schematic overview (Figure 3), including the AKT, its effectors, and all database lncRNAs mentioned, and show the points of the AKT pathway that they are involved in.  2.4.7. Potential future directions As described above, a literature survey connected AKT effector-targeting database lncRNAs to several cell functions. A careful inspection is still needed before performing more experiments to validate the targeting because they are the predicted candidates. It A deeper assessment for exploring the role of AKT effectors targeted by lncRNAs in regulating cancer cell functions is warranted.

Connecting AKT/AKT Effectors and CircRNAs to Cell Functions
In the following, the literature survey evidence to connect AKT and circRNAs to AKT signal-modulating cell functions (Figure 1) is described later (Section 3.1).
Notably, some circRNAs were reported to modulate the expressions of AKT1 [258], AKT2 [259], and AKT3 [260]. However, their potential mechanisms still warrant a detailed exploration, particularly for the possible targeting to AKT by circRNAs. Subsequently, the potential targeting to AKT1, AKT2, and AKT3 by circRNAs and their associated cell functions are discussed in Section 3.2. By choosing the circRNA database (circBase [61]), the target information of respective circRNAs was predicted, and their impacts on cell functions were evaluated, as described later.
Some circRNAs were reported to modulate the expressions of AKT effectors [61]. However, their connection to cell functions has never been investigated, especially for cancer cells. Hence, the evidence that connects the AKT effectors and circRNAs to their modulating cell functions (Figure 1) was evaluated by literature retrieval (Section 3.3). However, their potential mechanisms still warrant a detailed exploration, particularly for the possible targeting to AKT effectors by circRNAs. Subsequently, the potential targeting to AKT effectors by circRNAs and their associated cell functions are discussed in Section 3.4. By choosing the circRNA database (circBase [61]), the target information of respective circRNAs was predicted, and their impacts on cell functions were evaluated, as described later.

Potential Future Directions
As described above, a literature survey connected AKT effector-targeting database lncRNAs to several cell functions. A careful inspection is still needed before performing more experiments to validate the targeting because they are the predicted candidates. It A deeper assessment for exploring the role of AKT effectors targeted by lncRNAs in regulating cancer cell functions is warranted.

Connecting AKT/AKT Effectors and CircRNAs to Cell Functions
In the following, the literature survey evidence to connect AKT and circRNAs to AKT signal-modulating cell functions (Figure 1) is described later (Section 3.1).
Notably, some circRNAs were reported to modulate the expressions of AKT1 [258], AKT2 [259], and AKT3 [260]. However, their potential mechanisms still warrant a detailed exploration, particularly for the possible targeting to AKT by circRNAs. Subsequently, the potential targeting to AKT1, AKT2, and AKT3 by circRNAs and their associated cell functions are discussed in Section 3.2. By choosing the circRNA database (circBase [61]), the target information of respective circRNAs was predicted, and their impacts on cell functions were evaluated, as described later.
Some circRNAs were reported to modulate the expressions of AKT effectors [61]. However, their connection to cell functions has never been investigated, especially for cancer cells. Hence, the evidence that connects the AKT effectors and circRNAs to their modulating cell functions (Figure 1) was evaluated by literature retrieval (Section 3.3). However, their potential mechanisms still warrant a detailed exploration, particularly for the possible targeting to AKT effectors by circRNAs. Subsequently, the potential targeting to AKT effectors by circRNAs and their associated cell functions are discussed in Section 3.4. By choosing the circRNA database (circBase [61]), the target information of respective circRNAs was predicted, and their impacts on cell functions were evaluated, as described later.

Connecting AKT and CircRNAs to Cell Functions
AKT signaling and circRNAs have a cross-relationship regulating carcinogenesis [261][262][263]. AKT-regulating circRNAs are essential in controlling apoptosis, autophagy, ER stress, senescence, and migration. The connections between mitochondrial morphogenesis, ferroptosis, necroptosis, DNA damage response, and circRNAs are rarely reported. Therefore, these cell functions with regard to apoptosis, autophagy, ER stress, senescence, and migration connecting to circRNAs are described in Sections 3.1.1-3.1.6, especially for cancer cells.

ER Stress by AKT-Regulating CircRNAs
ER stress-modulating effects of circRNAs involving AKT have been reported in cancer cells. Overexpression of circCDR1as causes ER stress of oral cancer cells under a hypoxic microenvironment, accompanied by phosphorylating AKT [272]. A careful examination of ER stress influenced by more AKT-regulating circRNAs on cancer cells is warranted.

Senescence by AKT-Regulating CircRNAs
Senescence-modulating effects of circRNAs involving AKT have been reported. AKTregulating circRNAs may regulate the senescence of noncancerous cells. Circ_FOXO3 overexpression induces cardiac senescence, and circ_FOXO3 knockdown suppresses senescence of mouse embryonic fibroblasts [277]. By contrast, the role of AKT-regulating circRNAs in regulating the senescence of cancer cells was rarely reported. Notably, AKT phosphorylating downregulates FOXO3 during cancer development [278], and therefore the role of FOXO3 in the regulation of senescence involving AKT-regulating circ_FOXO3 needs to be examined in cancer cells. This warrants a detailed assessment of senescence influenced by more AKT-regulating circRNAs on cancer cells in the future.

Migration by AKT-Regulating CircRNAs
Migration-modulating effects of circRNAs involving AKT have been reported in cancer cells. The migration-promoting and -suppressing effects of circRNAs connecting to AKT have been investigated. S100A4 promotes the migration of esophageal cancer cells by phosphorylating AKT [279]. ZNF139/circZNF139 enhances the migration of bladder cancer cells by phosphorylating AKT [280]. Circ_0010882 stimulates the migration of gastric cancer cells by phosphorylating AKT [261]. Similarly, circ_0002984 promotes the migration of vascular smooth muscle cells by phosphorylating AKT [281]. In contrast, circ_100395 overexpression reduced the migration of papillary thyroid cancer cells by dephosphorylating AKT [282]. This warrants surveying more AKT-regulating circRNAs that regulate migration in the future.
3.1.6. Potential Future Directions As described above, several circRNAs were mentioned to regulate AKT phosphorylation or dephosphorylation for its activation and inactivation, thereby regulating cell functions. Overexpressing or downregulating these AKT-regulating circRNAs may reverse the status of cancer cell functions to improve the anticancer effects.
However, the cell function mechanism for the modulating effects of circRNAs on AKT remains unclear, particularly for the assessment of the potential targeting to AKT by circRNAs. More experiments are warranted to improve the connection between AKT-circRNAs regulating cancer cell functions.
Although respective circRNAs of AKT1, AKT2, and AKT3 genes were reported, the cell functions were not connected to the AKT1-, AKT2-, or AKT3-associated circRNAs in circBase [61]. Accordingly, we searched the literature via Google Scholar and PubMed and found novel information for networking the AKT1-, AKT2-, and AKT3-associated circRNAs and cell functions, especially for cancer cells.
Although many circRNAs were shown to target AKT1, AKT2, and AKT3, only some were capable of modulating cell functions (apoptosis and migration) in cancer cells based on the literature search. Several cell functions were not reported in AKT1, AKT2, and AKT3, such as autophagy, ER stress, mitochondrial morphogenesis, ferroptosis, necroptosis, DNA damage response, and senescence.
Several kinds of AKT1-, AKT2-, and AKT3-regulating circRNAs are overexpressed in many cancer cells. For example, circAKT1 (circ_0033550) is highly expressed in cervical cancer cells (Table 6) [283]. Circ_0033550 enhances cervical tumor growth. Transforming growth factor beta (TGF-β) can upregulate circ_0033550 to promote AKT1 and EMT expression in cervical cancer cells [283]. Accordingly, circAKT1 is a potential target to slow the progression of cervical cancer development.
In addition, circAKT2 (circ_0051079) is overexpressed in osteosarcoma tissues and cell lines and enhances their proliferation and metastasis (Table 6) [284]. In contrast, circAKT2 knockdown inhibits tumor growth of osteosarcoma.
Although the database provides many AKT-targeting circRNA candidates, most of them have rarely been investigated. A careful examination of more cell functions influenced by more AKT1-, AKT2-, and AKT3-targeting circRNAs on cancer cells is warranted. Overexpressing or downregulating these AKT-regulating database circRNAs may reverse the status of cancer cell functions to modulate their anticancer effects.

Connecting AKT Effectors and CircRNAs to Cell Functions
Since AKT had a cross-relationship to circRNAs as described above, the circRNAs may exhibit the impact on AKT effectors. In the following, we summarize the evidence connecting AKT effectors to circRNAs. Only some circRNAs were reported to regulate some AKT effectors (c-Myc, mTORC1, and HIF), and other AKT effectors (FOXO, S6K1, S6K2, 4EBP1, and SREBP1) were not reported. According to our literature survey (Google Scholar and PubMed), only some circRNAs could modulate cell functions (apoptosis, autophagy, and migration) (Sections 3.3.1-3.3.4), especially for cancer cells. Several cell functions were not reported in AKT effectors, such as ER stress, mitochondrial morphogenesis, ferroptosis, necroptosis, DNA damage response, and senescence, which were not listed.

Apoptosis and Migration by AKT Effector (c-Myc)-Regulating CircRNAs
As mentioned above, the relationship between c-Myc, circRNAs, and cell functions was rarely reported, except for apoptosis and migration. Some circRNAs can regulate apoptosis of cancer cells involving c-Myc. CircPVT1 silencing enhances apoptosis of acute lymphoblastic leukemia cells by downregulating c-Myc [289]. CircRHOT1 knockdown triggers apoptosis of lung cancer cells by decreasing c-Myc expression [290].
Additionally, some circRNAs can regulate migration involving c-Myc. The migrationpromoting and -suppressing effects of circRNA connecting to c-Myc were reported in cancer cells. Several kinds of c-Myc-regulating circRNAs are overexpressed in many cancer cells. Modulating circRNAs may improve the anticancer effects by suppressing migration. For example, circZFR is overexpressed in liver cancer cells [291]. CircZFR knockdown inhibits the migration of liver cancer cells by downregulating c-Myc expression [291]. Similarly, circRNA_010763 is highly expressed in lung cancer cells. CircRNA_010763 improves the invasion of lung cancer cells by upregulating c-Myc expression [292]. Circ_NOTCH1 is overexpressed in nasopharyngeal [293] and gastric [294] cancer cells. Circ_NOTCH1 silencing inhibits the migration of nasopharyngeal cancer cells, where c-Myc can bind to the NOTCH1 promoter to transcriptionally activate circ_NOTCH1 [293]. Similarly, circ_NOTCH1 enhances metastasis of gastric cancer cells [294]. CircCCDC66 silencing decreases the migration of gastric cancer cells by downregulating c-Myc expression [295]. In contrast, circCDYL overexpression by plasmids blocks the migration of bladder cancer cells by reducing c-Myc expression [296]. Surveying more c-Myc-regulating circRNAs that control apoptosis and migration is warranted.
3.3.2. Apoptosis, Autophagy, and Migration by AKT Effector (mTORC1)-Regulating CircRNAs As mentioned above, the relationship between mTORC1, circRNAs, and cell functions was rarely reported, except for apoptosis, autophagy, and migration. Several kinds of mTORC1-regulating circRNAs are overexpressed in many cancer cells. Some circRNAs can regulate apoptosis involving mTORC1. Circ_ZNF512 knockdown inhibits apoptosis to reduce myocardial tissue injury by downregulating mTORC1 [297].
Some circRNAs can regulate migration involving mTORC1. LDLRAD3 silencing decreases the migration of lung cancer cells by dephosphorylating mTOR for mTORC1 inactivation [299]. A connection between migration, mTORC2, and cicrRNAs has not been published as yet. Surveying more mTORC1-regulating circRNAs that control apoptosis is warranted.

Apoptosis and Migration by AKT Effector (HIF)-Regulating CircRNAs
Some circRNAs can regulate apoptosis involving HIF. The apoptosis-promoting and -suppressing effects of circRNA connecting to HIF were reported. CircVEGFC improves high glucose-promoted apoptosis of vascular endothelial cells by downregulating HIF1A [300]. Circ_0010729 suppresses apoptosis of vascular endothelial cells by upregulating HIF1A [301]. In contrast, circRNA_100859 is overexpressed in colon cancer tissues and suppresses apoptosis by downregulating HIF1A [302].
Some circRNAs can regulate migration involving HIF. The migration-promoting and suppressing effects of circRNA connecting to HIF were reported. Several kinds of HIFregulating circRNAs, such as circAGFG1, circASXL1, circ-0046600, and circPVT1, are overexpressed in many cancer cells [303][304][305][306]. Modulating HIF1A can regulate the levels of certain circRNAs. For example, circAGFG1 is highly expressed in lung cancer cells. CircAGFG1 enhances the migration of lung cancer cells by upregulating HIF1A [303]. Inhibition of circASXL1 blocks migration and HIF1A expression of lung cancer cells [304]. Circ-0046600 knockdown suppresses the migration of liver cancer cells by upregulating HIF1A [305]. Overexpressed circPVT1 enhances the migration of breast cancer cells by overexpressing HIF1A [306]. In contrast, HIF1A-regulating circRNA such as circ_EPHB4 is downregulated in cancer cells. Overexpression of circ_EPHB4, exhibiting low levels in liver cancer cells, suppressed the migration by downregulating HIF1A [307]. Surveying more HIF-regulating circRNAs that control apoptosis is warranted.

Potential Future Directions
As described above, several circRNAs were mentioned to regulate AKT effectors and, in turn, control cell functions. Overexpressing or downregulating these AKT effectorregulating circRNAs may reverse the status of cancer cell functions to improve anticancer effects.
However, the cell function mechanism for the modulating effects of circRNAs on AKT effectors remains unclear, particularly for the assessment of the potential targeting to AKT effectors by circRNAs. More experiments are warranted to improve the connection between AKT effectors and circRNAs regulating cancer cell functions.
In addition to Section 3.3, several circRNAs also target AKT effectors, but their relationship to cell function is not reported. Some circRNA target information to AKT effectors was retrieved from circBase [61] (Table 7). Table 7. AKT effector-targeting database circRNAs.
indicates not available in the circBase database (accessed on 13 June 2022). CircRNAs in bold were reported in the literature, as described later.
Interestingly, the AKT effector-targeting circRNAs do not overlap (Table 7). Although the respective circRNAs of these AKT effectors were reported, the cell functions were not connected to these AKT effector-associated circRNAs.
Here, we summarize the literature search on Google Scholar and PubMed, which provided novel information for networking these AKT effector-associated circRNAs and cell functions (Table 8). Several cell functions were not reported in AKT effectors, such as autophagy, ER stress, mitochondrial morphogenesis, ferroptosis, necroptosis, DNA damage response, and senescence, which were not listed (Table 8). For example, circMYC (circ_0085533) is more expressed in melanoma tissues than in normal tissues [308]. CircMYC knockdown suppresses cell proliferation and apoptosis of melanoma cells, reverted by circMYC overexpression [308] (Table 8).
circmTOR (circ_0009805) is overexpressed in severe preeclamptic placentas [309]. CircmTOR (circ_0009792) is upregulated in the proliferation of vascular smooth muscle cells [310] (Table 8). Other cell functions were rarely reported for this circmTOR. This warrants a detailed investigation of more cell functions involving circmTOR. circAKT1S1 (circ_0000950) is highly expressed in the cell models of Alzheimer's disease. CircAKT1S1 induces apoptosis of neuron cells [311]. CircAKT1S1 silencing promotes proliferation and suppresses apoptosis of neurons [312] (Table 8). Accordingly, it is a potential target to slow down the progression of Alzheimer's disease.
Although the database provides many AKT-targeting circRNA candidates, most of them were rarely investigated. Only a few AKT effector-targeting circRNAs were reported to connect to some functions of cancer and noncancer cells. This warrants a detailed evaluation of more cancer cell functions in AKT effector-targeting circRNAs in the future. Overexpressing or downregulating these AKT effector-regulating database circRNAs may reverse the status of cancer cell function to improve anticancer effects.

Conclusions
Several lncRNAs and circRNAs may regulate numerous pathways and control diverse cell functions, which are not unique to AKT and AKT effectors. For the sake of their critical regulations, as mentioned above, this review focused on AKT and AKT effectors modulating by lncRNAs and circRNAs; however, the impact of lncRNAs and circRNAs on AKT and AKT effectors in modulating cell function remains unclear. This systematic review aimed to organize the current knowledge for connecting AKT and AKT effectors to lncRNAs and circRNAs. The collected literature herein suggests that these AKT-lncRNA, AKTeffector lncRNA, AKT circRNA, and AKT-effector circRNA connections are responsible for regulating several cancer cell functions.
Databases for lncRNAs and circRNAs, such as LincTarD and circBase, provide comprehensive AKT-and AKT effector-targeting candidates for lncRNAs and circRNAs. However, their impacts on cell functions were not provided in these databases. Accordingly, the potential regulation of cell functions for more AKT-and AKT effector-targeting lncRNAs and circRNAs warrants a detailed investigation. Our literature survey shows that these AKT-and AKT effector-targeting database lncRNAs and circRNAs are organized and connected to cancer cell functions. Notably, database-predicted AKT-and AKT effectortargeting lncRNAs and circRNAs may be derived from the literature on some cancer cell lines. Since the genetic profiles of different cancer cells are different, the database-predicted lncRNAs and circRNAs candidates for AKT and AKT effectors may be limited to some cancer cell types but not others. Similarly, the organized cell functions for the AKT-and AKT effector-regulating or -targeting lncRNAs and circRNAs were also reported from different cancer cells or specific environments. Careful assessment is still required where the targeting mechanisms are concerned.
Two gaps are still present in the present review. Several lncRNAs that regulate AKT and AKT effectors were surveyed and provided a reliable connection between each other. Although the emerging evidence was collected to provide updated information, these literature-survey lncRNAs still lack the potential targeting information. Another gap is the systemic update for the databases. It is possible that some new findings or data were not immediately updated in LncTarD or circBase. Hence, more experiments to provide validated information for mechanisms regulating AKT, AKT effectors, lncRNAs, and circRNAs are required in order to fill these gaps. Consequently, the validated information can provide the resource for updating the databases for lncRNAs and circRNAs.
In conclusion, this review provides relevant information for relating lncRNAs and circRNAs to AKT and its effectors in modulating several cancer cell functions. With the help of bioinformatics and a literature survey, the detailed mechanism of targeting information to AKT and AKT effectors was well connected to lncRNAs and circRNAs and organized to regulate cell functions. This work also sheds light on AKT-signaling studies investigating potential impacts on lncRNAs and circRNAs for regulating cancer cell functions.  Acknowledgments: The authors thank our colleague Hans-Uwe Dahms for editing the manuscript.

Conflicts of Interest:
The authors declare that there are no conflicts of interest.