The Emerging Role of m6A Modification in Endocrine Cancer
Abstract
:Simple Summary
Abstract
1. Introduction
2. M6A Methyltransferase
2.1. Writers
2.2. Erasers
2.3. Readers
3. m6A Modification and Cancer
3.1. Thyroid Carcinoma
3.2. Ovarian Cancer
3.3. Pancreatic Cancer
4. Pituitary Adenoma
5. The Future Perspectives on the Application of Targeted m6A Therapy in the Treatment of Endocrine Cancer
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Schulte, K.M.; Gill, A.J.; Barczynski, M.; Karakas, E.; Miyauchi, A.; Knoefel, W.T.; Lombardi, C.P.; Talat, N.; Diaz-Cano, S.; Grant, C.S. Classification of parathyroid cancer. Ann. Surg. Oncol. 2012, 19, 2620–2628. [Google Scholar] [CrossRef] [PubMed]
- Wong, J.; Fulp, W.J.; Strosberg, J.R.; Kvols, L.K.; Centeno, B.A.; Hodul, P.J. Predictors of lymph node metastases and impact on survival in resected pancreatic neuroendocrine tumors: A single-center experience. Am. J. Surg. 2014, 208, 775–780. [Google Scholar] [CrossRef]
- Sav, A.; Rotondo, F.; Syro, L.V.; Di Ieva, A.; Cusimano, M.D.; Kovacs, K. Invasive, atypical and aggressive pituitary adenomas and carcinomas. Endocrinol. Metab. Clin. N. Am. 2015, 44, 99–104. [Google Scholar] [CrossRef] [PubMed]
- Xu, J.Y.; Handy, B.; Michaelis, C.L.; Waguespack, S.G.; Hu, M.I.; Busaidy, N.; Jimenez, C.; Cabanillas, M.E.; Fritsche, H.J.; Cote, G.J.; et al. Detection and Prognostic Significance of Circulating Tumor Cells in Patients With Metastatic Thyroid Cancer. J. Clin. Endocrinol. Metab. 2016, 101, 4461–4467. [Google Scholar] [CrossRef] [PubMed]
- Scollo, C.; Russo, M.; Trovato, M.A.; Sambataro, D.; Giuffrida, D.; Manusia, M.; Sapuppo, G.; Malandrino, P.; Vigneri, R.; Pellegriti, G. Prognostic Factors for Adrenocortical Carcinoma Outcomes. Front. Endocrinol. 2016, 7, 99. [Google Scholar] [CrossRef]
- Roignant, J.Y.; Soller, M. m(6)A in mRNA: An Ancient Mechanism for Fine-Tuning Gene Expression. Trend Genet. 2017, 33, 380–390. [Google Scholar] [CrossRef]
- Desrosiers, R.; Friderici, K.; Rottman, F. Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. Proc. Natl. Acad. Sci. USA 1974, 71, 3971–3975. [Google Scholar] [CrossRef]
- Oerum, S.; Meynier, V.; Catala, M.; Tisné, C. A comprehensive review of m6A/m6Am RNA methyltransferase structures. Nucleic Acids Res. 2021, 21, 7239–7255. [Google Scholar] [CrossRef]
- Mauer, J.; Luo, X.; Blanjoie, A.; Jiao, X.; Grozhik, A.V.; Patil, D.P.; Linder, B.; Pickering, B.F.; Vasseur, J.J.; Chen, Q.; et al. Reversible methylation of m(6)A(m) in the 5′ cap controls mRNA stability. Nature 2017, 541, 371–375. [Google Scholar] [CrossRef]
- Wang, X.; He, C. Reading RNA methylation codes through methyl-specific binding proteins. RNA Biol. 2014, 11, 669–672. [Google Scholar] [CrossRef] [Green Version]
- He, L.; Li, H.; Wu, A.; Peng, Y.; Shu, G.; Yin, G. Functions of N6-methyladenosine and its role in cancer. Mol. Cancer 2019, 18, 176. [Google Scholar] [CrossRef]
- Bokar, J.A.; Rath-Shambaugh, M.E.; Ludwiczak, R.; Narayan, P.; Rottman, F. Characterization and partial purification of mRNA N6-adenosine methyltransferase from HeLa cell nuclei. Internal mRNA methylation requires a multisubunit complex. J. Biol. Chem. 1994, 269, 17697–17704. [Google Scholar] [CrossRef]
- Wang, P.; Doxtader, K.A.; Nam, Y. Structural Basis for Cooperative Function of Mettl3 and Mettl14 Methyltransferases. Mol. Cell 2016, 63, 306–317. [Google Scholar] [CrossRef] [PubMed]
- Wang, X.; Huang, J.; Zou, T.; Yin, P. Human m(6)A writers: Two subunits, 2 roles. RNA Biol. 2017, 14, 300–304. [Google Scholar] [CrossRef] [PubMed]
- Wang, X.; Feng, J.; Xue, Y.; Guan, Z.; Zhang, D.; Liu, Z.; Gong, Z.; Wang, Q.; Huang, J.; Tang, C.; et al. Structural basis of N(6)-adenosine methylation by the METTL3-METTL14 complex. Nature 2016, 534, 575–578. [Google Scholar] [CrossRef] [PubMed]
- Warda, A.S.; Kretschmer, J.; Hackert, P.; Lenz, C.; Urlaub, H.; Höbartner, C.; Sloan, K.E.; Bohnsack, M.T. Human METTL16 is a N(6)-methyladenosine (m(6)A) methyltransferase that targets pre-mRNAs and various non-coding RNAs. EMBO Rep. 2017, 18, 2004–2014. [Google Scholar] [CrossRef] [PubMed]
- Shima, H.; Matsumoto, M.; Ishigami, Y.; Ebina, M.; Muto, A.; Sato, Y.; Kumagai, S.; Ochiai, K.; Suzuki, T.; Igarashi, K. S-Adenosylmethionine Synthesis Is Regulated by Selective N(6)-Adenosine Methylation and mRNA Degradation Involving METTL16 and YTHDC1. Cell Rep. 2017, 21, 3354–3363. [Google Scholar] [CrossRef]
- Thomas, J.M.; Batista, P.J.; Meier, J.L. Metabolic Regulation of the Epitranscriptome. ACS Chem. Biol. 2019, 14, 316–324. [Google Scholar] [CrossRef]
- Pendleton, K.E.; Chen, B.; Liu, K.; Hunter, O.V.; Xie, Y.; Tu, B.P.; Conrad, N.K. The U6 snRNA m(6)A Methyltransferase METTL16 Regulates SAM Synthetase Intron Retention. Cell 2017, 169, 824–835. [Google Scholar] [CrossRef]
- van Tran, N.; Ernst, F.; Hawley, B.R.; Zorbas, C.; Ulryck, N.; Hackert, P.; Bohnsack, K.E.; Bohnsack, M.T.; Jaffrey, S.R.; Graille, M.; et al. The human 18S rRNA m6A methyltransferase METTL5 is stabilized by TRMT112. Nucleic Acids Res. 2019, 47, 7719–7733. [Google Scholar] [CrossRef] [Green Version]
- Richard, E.M.; Polla, D.L.; Assir, M.Z.; Contreras, M.; Shahzad, M.; Khan, A.A.; Razzaq, A.; Akram, J.; Tarar, M.N.; Blanpied, T.A.; et al. Bi-allelic Variants in METTL5 Cause Autosomal-Recessive Intellectual Disability and Microcephaly. Am. J. Hum. Genet. 2019, 105, 869–878. [Google Scholar] [CrossRef]
- Ping, X.L.; Sun, B.F.; Wang, L.; Xiao, W.; Yang, X.; Wang, W.J.; Adhikari, S.; Shi, Y.; Lv, Y.; Chen, Y.S.; et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 2014, 24, 177–189. [Google Scholar] [CrossRef]
- Liu, J.; Yue, Y.; Han, D.; Wang, X.; Fu, Y.; Zhang, L.; Jia, G.; Yu, M.; Lu, Z.; Deng, X.; et al. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat. Chem. Biol. 2014, 10, 93–95. [Google Scholar] [CrossRef] [PubMed]
- Patil, D.P.; Chen, C.K.; Pickering, B.F.; Chow, A.; Jackson, C.; Guttman, M.; Jaffrey, S.R. m(6)A RNA methylation promotes XIST-mediated transcriptional repression. Nature 2016, 537, 369–373. [Google Scholar] [CrossRef] [PubMed]
- Knuckles, P.; Lence, T.; Haussmann, I.U.; Jacob, D.; Kreim, N.; Carl, S.H.; Masiello, I.; Hares, T.; Villaseñor, R.; Hess, D.; et al. Zc3h13/Flacc is required for adenosine methylation by bridging the mRNA-binding factor Rbm15/Spenito to the m(6)A machinery component Wtap/Fl(2)d. Genes Dev. 2018, 32, 415–429. [Google Scholar] [CrossRef] [PubMed]
- Schöller, E.; Weichmann, F.; Treiber, T.; Ringle, S.; Treiber, N.; Flatley, A.; Feederle, R.; Bruckmann, A.; Meister, G. Interactions, localization, and phosphorylation of the m(6)A generating METTL3-METTL14-WTAP complex. RNA 2018, 24, 499–512. [Google Scholar] [CrossRef]
- Wen, J.; Lv, R.; Ma, H.; Shen, H.; He, C.; Wang, J.; Jiao, F.; Liu, H.; Yang, P.; Tan, L.; et al. Zc3h13 Regulates Nuclear RNA m(6)A Methylation and Mouse Embryonic Stem Cell Self-Renewal. Mol. Cell 2018, 69, 1028–1038. [Google Scholar] [CrossRef]
- Yue, Y.; Liu, J.; Cui, X.; Cao, J.; Luo, G.; Zhang, Z.; Cheng, T.; Gao, M.; Shu, X.; Ma, H.; et al. VIRMA mediates preferential m(6)A mRNA methylation in 3 ′UTR and near stop codon and associates with alternative polyadenylation. Cell Discov. 2018, 4, 10. [Google Scholar] [CrossRef]
- Ma, H.; Wang, X.; Cai, J.; Dai, Q.; Natchiar, S.K.; Lv, R.; Chen, K.; Lu, Z.; Chen, H.; Shi, Y.G.; et al. N(6-)Methyladenosine methyltransferase ZCCHC4 mediates ribosomal RNA methylation. Nat. Chem. Biol. 2019, 15, 88–94. [Google Scholar] [CrossRef]
- Zheng, G.; Dahl, J.A.; Niu, Y.; Fedorcsak, P.; Huang, C.M.; Li, C.J.; Vågbø, C.B.; Shi, Y.; Wang, W.L.; Song, S.H.; et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol. Cell 2013, 49, 18–29. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jia, G.; Fu, Y.; Zhao, X.; Dai, Q.; Zheng, G.; Yang, Y.; Yi, C.; Lindahl, T.; Pan, T.; Yang, Y.G.; et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat. Chem. Biol. 2011, 7, 885–887. [Google Scholar] [CrossRef]
- Dina, C.; Meyre, D.; Gallina, S.; Durand, E.; Körner, A.; Jacobson, P.; Carlsson, L.M.; Kiess, W.; Vatin, V.; Lecoeur, C.; et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat. Genet. 2007, 39, 724–726. [Google Scholar] [CrossRef]
- Frayling, T.M.; Timpson, N.J.; Weedon, M.N.; Zeggini, E.; Freathy, R.M.; Lindgren, C.M.; Perry, J.R.; Elliott, K.S.; Lango, H.; Rayner, N.W.; et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007, 316, 889–894. [Google Scholar] [CrossRef]
- Scuteri, A.; Sanna, S.; Chen, W.M.; Uda, M.; Albai, G.; Strait, J.; Najjar, S.; Nagaraja, R.; Orrú, M.; Usala, G.; et al. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet. 2007, 3, e115. [Google Scholar] [CrossRef]
- Aik, W.; Scotti, J.S.; Choi, H.; Gong, L.; Demetriades, M.; Schofield, C.J.; McDonough, M.A. Structure of human RNA N⁶-methyladenine demethylase ALKBH5 provides insights into its mechanisms of nucleic acid recognition and demethylation. Nucleic Acids Res. 2014, 42, 4741–4754. [Google Scholar] [CrossRef] [PubMed]
- Chen, W.; Zhang, L.; Zheng, G.; Fu, Y.; Ji, Q.; Liu, F.; Chen, H.; He, C. Crystal structure of the RNA demethylase ALKBH5 from zebrafish. FEBS Lett. 2014, 588, 892–898. [Google Scholar] [CrossRef]
- Sun, T.; Wu, R.; Ming, L. The role of m6A RNA methylation in cancer. Biomed. Pharmacother. 2019, 112, 108613. [Google Scholar] [CrossRef] [PubMed]
- Ueda, Y.; Ooshio, I.; Fusamae, Y.; Kitae, K.; Kawaguchi, M.; Jingushi, K.; Hase, H.; Harada, K.; Hirata, K.; Tsujikawa, K. AlkB homolog 3-mediated tRNA demethylation promotes protein synthesis in cancer cells. Sci. Rep. 2017, 7, 42271. [Google Scholar] [CrossRef] [PubMed]
- Zaccara, S.; Jaffrey, S.R. A Unified Model for the Function of YTHDF Proteins in Regulating m6A-Modified mRNA. Cell. 2020, 25, 1582–1595. [Google Scholar] [CrossRef] [PubMed]
- Meyer, K.D.; Jaffrey, S.R. Rethinking m(6)A Readers, Writers, and Erasers. Annu. Rev. Cell Dev. Biol. 2017, 33, 319–342. [Google Scholar] [CrossRef] [Green Version]
- Du, H.; Zhao, Y.; He, J.; Zhang, Y.; Xi, H.; Liu, M.; Ma, J.; Wu, L. YTHDF2 destabilizes m(6)A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex. Nat. Commun. 2016, 7, 12626. [Google Scholar] [CrossRef]
- Zhu, T.; Roundtree, I.A.; Wang, P.; Wang, X.; Wang, L.; Sun, C.; Tian, Y.; Li, J.; He, C.; Xu, Y. Crystal structure of the YTH domain of YTHDF2 reveals mechanism for recognition of N6-methyladenosine. Cell Res. 2014, 24, 1493–1496. [Google Scholar] [CrossRef] [PubMed]
- Shi, H.; Wang, X.; Lu, Z.; Zhao, B.S.; Ma, H.; Hsu, P.J.; Liu, C.; He, C. YTHDF3 facilitates translation and decay of N(6)-methyladenosine-modified RNA. Cell Res. 2017, 27, 315–328. [Google Scholar] [CrossRef] [PubMed]
- Wang, X.; Lu, Z.; Gomez, A.; Hon, G.C.; Yue, Y.; Han, D.; Fu, Y.; Parisien, M.; Dai, Q.; Jia, G.; et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature 2014, 505, 117–120. [Google Scholar] [CrossRef] [PubMed]
- Li, A.; Chen, Y.S.; Ping, X.L.; Yang, X.; Xiao, W.; Yang, Y.; Sun, H.Y.; Zhu, Q.; Baidya, P.; Wang, X.; et al. Cytoplasmic m(6)A reader YTHDF3 promotes mRNA translation. Cell Res. 2017, 27, 444–447. [Google Scholar] [CrossRef] [PubMed]
- Huang, H.; Weng, H.; Sun, W.; Qin, X.; Shi, H.; Wu, H.; Zhao, B.S.; Mesquita, A.; Liu, C.; Yuan, C.L.; et al. Recognition of RNA N(6)-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat. Cell Biol. 2018, 20, 285–295. [Google Scholar] [CrossRef]
- Wang, X.; Zhao, B.S.; Roundtree, I.A.; Lu, Z.; Han, D.; Ma, H.; Weng, X.; Chen, K.; Shi, H.; He, C. N(6)-methyladenosine Modulates Messenger RNA Translation Efficiency. Cell 2015, 161, 1388–1399. [Google Scholar] [CrossRef]
- Xiao, W.; Adhikari, S.; Dahal, U.; Chen, Y.S.; Hao, Y.J.; Sun, B.F.; Sun, H.Y.; Li, A.; Ping, X.L.; Lai, W.Y.; et al. Nuclear m(6)A Reader YTHDC1 Regulates mRNA Splicing. Mol. Cell 2016, 61, 507–519. [Google Scholar] [CrossRef]
- Roundtree, I.A.; Luo, G.Z.; Zhang, Z.; Wang, X.; Zhou, T.; Cui, Y.; Sha, J.; Huang, X.; Guerrero, L.; Xie, P.; et al. YTHDC1 mediates nuclear export of N(6)-methyladenosine methylated mRNAs. eLife 2017, 6, e31311. [Google Scholar] [CrossRef]
- Lesbirel, S.; Viphakone, N.; Parker, M.; Parker, J.; Heath, C.; Sudbery, I.; Wilson, S.A. The m(6)A-methylase complex recruits TREX and regulates mRNA export. Sci. Rep. 2018, 8, 13827. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wojtas, M.N.; Pandey, R.R.; Mendel, M.; Homolka, D.; Sachidanandam, R.; Pillai, R.S. Regulation of m(6)A Transcripts by the 3′→5′ RNA Helicase YTHDC2 Is Essential for a Successful Meiotic Program in the Mammalian Germline. Mol. Cell 2017, 68, 374–387. [Google Scholar] [CrossRef]
- Hsu, P.J.; Zhu, Y.; Ma, H.; Guo, Y.; Shi, X.; Liu, Y.; Qi, M.; Lu, Z.; Shi, H.; Wang, J.; et al. Ythdc2 is an N(6)-methyladenosine binding protein that regulates mammalian spermatogenesis. Cell Res. 2017, 27, 1115–1127. [Google Scholar] [CrossRef] [PubMed]
- Alarcón, C.R.; Goodarzi, H.; Lee, H.; Liu, X.; Tavazoie, S.; Tavazoie, S.F. HNRNPA2B1 Is a Mediator of m(6)A-Dependent Nuclear RNA Processing Events. Cell 2015, 162, 1299–1308. [Google Scholar] [CrossRef]
- Alarcón, C.R.; Lee, H.; Goodarzi, H.; Halberg, N.; Tavazoie, S.F. N6-methyladenosine marks primary microRNAs for processing. Nature 2015, 519, 482–485. [Google Scholar] [CrossRef]
- Liu, N.; Dai, Q.; Zheng, G.; He, C.; Parisien, M.; Pan, T. N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature 2015, 518, 560–564. [Google Scholar] [CrossRef]
- Liu, N.; Zhou, K.I.; Parisien, M.; Dai, Q.; Diatchenko, L.; Pan, T. N6-methyladenosine alters RNA structure to regulate binding of a low-complexity protein. Nucleic Acids Res. 2017, 45, 6051–6063. [Google Scholar] [CrossRef] [PubMed]
- Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2018. Cancer J. Clin. 2018, 68, 7–30. [Google Scholar] [CrossRef] [PubMed]
- Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef]
- Miranda-Filho, A.; Lortet-Tieulent, J.; Bray, F.; Cao, B.; Franceschi, S.; Vaccarella, S.; Dal Maso, L. Thyroid cancer incidence trends by histology in 25 countries: A population-based study. Lancet Diabetes Endocrinol. 2021, 9, 225–234. [Google Scholar] [CrossRef]
- LiVolsi, V.A. Papillary thyroid carcinoma: An update. Mod. Pathol. 2011, 24 (Suppl. S2), S1–S9. [Google Scholar] [CrossRef] [Green Version]
- Omur, O.; Baran, Y. An update on molecular biology of thyroid cancers. Crit. Rev. Oncol. Hematol. 2014, 90, 233–252. [Google Scholar] [CrossRef]
- Rosenbaum, M.A.; McHenry, C.R. Contemporary management of papillary carcinoma of the thyroid gland. Expert Rev. Anticancer Ther. 2009, 9, 317–329. [Google Scholar] [CrossRef] [PubMed]
- Huang, Y.; Prasad, M.; Lemon, W.J.; Hampel, H.; Wright, F.A.; Kornacker, K.; LiVolsi, V.; Frankel, W.; Kloos, R.T.; Eng, C.; et al. Gene expression in papillary thyroid carcinoma reveals highly consistent profiles. Proc. Natl. Acad. Sci. USA 2001, 98, 15044–15049. [Google Scholar] [CrossRef]
- Nixon, I.J.; Simo, R.; Newbold, K.; Rinaldo, A.; Suarez, C.; Kowalski, L.P.; Silver, C.; Shah, J.P.; Ferlito, A. Management of Invasive Differentiated Thyroid Cancer. Thyroid 2016, 26, 1156–1166. [Google Scholar] [CrossRef]
- Fröhlich, E.; Wahl, R. The current role of targeted therapies to induce radioiodine uptake in thyroid cancer. Cancer Treat. Rev. 2014, 40, 665–674. [Google Scholar] [CrossRef]
- Li, X.; Abdel-Mageed, A.B.; Kandil, E. BRAF mutation in papillary thyroid carcinoma. Int. J. Clin. Exp. Med. 2012, 5, 310–315. [Google Scholar]
- Li, X.; Abdel-Mageed, A.B.; Mondal, D.; Kandil, E. The nuclear factor kappa-B signaling pathway as a therapeutic target against thyroid cancers. Thyroid 2013, 23, 209–218. [Google Scholar] [CrossRef] [PubMed]
- Zhu, Y.; Peng, X.; Zhou, Q.; Tan, L.; Zhang, C.; Lin, S.; Long, M. METTL3-mediated m6A modification of STEAP2 mRNA inhibits papillary thyroid cancer progress by blocking the Hedgehog signaling pathway and epithelial-to-mesenchymal transition. Cell Death Dis. 2022, 13, 358. [Google Scholar] [CrossRef] [PubMed]
- He, J.; Zhou, M.; Yin, J.; Wan, J.; Chu, J.; Jia, J.; Sheng, J.; Wang, C.; Yin, H.; He, F. METTL3 restrains papillary thyroid cancer progression via m(6)A/c-Rel/IL-8-mediated neutrophil infiltration. Mol. Ther. 2021, 29, 1821–1837. [Google Scholar] [CrossRef]
- Wang, K.; Jiang, L.; Zhang, Y.; Chen, C. Progression of Thyroid Carcinoma Is Promoted by the m6A Methyltransferase METTL3 Through Regulating m(6)A Methylation on TCF1. OncoTargets Ther. 2020, 13, 1605–1612. [Google Scholar] [CrossRef] [PubMed]
- Lin, S.; Zhu, Y.; Ji, C.; Yu, W.; Zhang, C.; Tan, L.; Long, M.; Luo, D.; Peng, X. METTL3-Induced miR-222-3p Upregulation Inhibits STK4 and Promotes the Malignant Behaviors of Thyroid Carcinoma Cells. J. Clin. Endocrinol. Metab. 2022, 107, 474–490. [Google Scholar] [CrossRef] [PubMed]
- Huang, J.; Sun, W.; Wang, Z.; Lv, C.; Zhang, T.; Zhang, D.; Dong, W.; Shao, L.; He, L.; Ji, X.; et al. FTO suppresses glycolysis and growth of papillary thyroid cancer via decreasing stability of APOE mRNA in an N6-methyladenosine-dependent manner. J. Exp. Clin. Cancer Res. 2022, 41, 42. [Google Scholar] [CrossRef] [PubMed]
- Ji, F.H.; Fu, X.H.; Li, G.Q.; He, Q.; Qiu, X.G. FTO Prevents Thyroid Cancer Progression by SLC7A11 m6A Methylation in a Ferroptosis-Dependent Manner. Front. Endocrinol. 2022, 13, 857765. [Google Scholar] [CrossRef]
- Sa, R.; Liang, R.; Qiu, X.; He, Z.; Liu, Z.; Chen, L. IGF2BP2-dependent activation of ERBB2 signaling contributes to acquired resistance to tyrosine kinase inhibitor in differentiation therapy of radioiodine-refractory papillary thyroid cancer. Cancer Lett. 2022, 527, 10–23. [Google Scholar] [CrossRef]
- Sa, R.; Liang, R.; Qiu, X.; He, Z.; Liu, Z.; Chen, L. Targeting IGF2BP2 Promotes Differentiation of Radioiodine Refractory Papillary Thyroid Cancer via Destabilizing RUNX2 mRNA. Cancers 2022, 14, 1268. [Google Scholar] [CrossRef]
- Ye, M.; Dong, S.; Hou, H.; Zhang, T.; Shen, M. Oncogenic Role of Long Noncoding RNAMALAT1 in Thyroid Cancer Progression through Regulation of the miR-204/IGF2BP2/m6A-MYC Signaling. Mol. Ther. Nucleic Acids 2021, 23, 1–12. [Google Scholar] [CrossRef]
- Dong, L.; Geng, Z.; Liu, Z.; Tao, M.; Pan, M.; Lu, X. IGF2BP2 knockdown suppresses thyroid cancer progression by reducing the expression of long non-coding RNA HAGLR. Pathol. Res. Pract. 2021, 225, 153550. [Google Scholar] [CrossRef]
- Bi, X.; Lv, X.; Liu, D.; Guo, H.; Yao, G.; Wang, L.; Liang, X.; Yang, Y. METTL3-mediated maturation of miR-126-5p promotes ovarian cancer progression via PTEN-mediated PI3K/Akt/mTOR pathway. Cancer Gene Ther. 2021, 28, 335–349. [Google Scholar] [CrossRef]
- Hua, W.; Zhao, Y.; Jin, X.; Yu, D.; He, J.; Xie, D.; Duan, P. METTL3 promotes ovarian carcinoma growth and invasion through the regulation of AXL translation and epithelial to mesenchymal transition. Gynecol. Oncol. 2018, 151, 356–365. [Google Scholar] [CrossRef]
- Li, Y.; Peng, H.; Jiang, P.; Zhang, J.; Zhao, Y.; Feng, X.; Pang, C.; Ren, J.; Zhang, H.; Bai, W.; et al. Downregulation of Methyltransferase-Like 14 Promotes Ovarian Cancer Cell Proliferation Through Stabilizing TROAP mRNA. Front. Oncol. 2022, 12, 824258. [Google Scholar] [CrossRef]
- Lyu, Y.; Zhang, Y.; Wang, Y.; Luo, Y.; Ding, H.; Li, P.; Ni, G. HIF-1α Regulated WTAP Overexpression Promoting the Warburg Effect of Ovarian Cancer by m6A-Dependent Manner. J. Immunol. Res. 2022, 2022, 6130806. [Google Scholar] [CrossRef]
- Nie, S.; Zhang, L.; Liu, J.; Wan, Y.; Jiang, Y.; Yang, J.; Sun, R.; Ma, X.; Sun, G.; Meng, H.; et al. ALKBH5-HOXA10 loop-mediated JAK2 m6A demethylation and cisplatin resistance in epithelial ovarian cancer. J. Exp. Clin. Cancer Res. 2021, 40, 284. [Google Scholar] [CrossRef] [PubMed]
- Jiang, Y.; Wan, Y.; Gong, M.; Zhou, S.; Qiu, J.; Cheng, W. RNA demethylase ALKBH5 promotes ovarian carcinogenesis in a simulated tumour microenvironment through stimulating NF-κB pathway. J. Cell. Mol. Med. 2020, 24, 6137–6148. [Google Scholar] [CrossRef]
- Huang, H.; Wang, Y.; Kandpal, M.; Zhao, G.; Cardenas, H.; Ji, Y.; Chaparala, A.; Tanner, E.J.; Chen, J.; Davuluri, R.V.; et al. FTO-Dependent N (6)-Methyladenosine Modifications Inhibit Ovarian Cancer Stem Cell Self-Renewal by Blocking cAMP Signaling. Cancer Res. 2020, 80, 3200–3214. [Google Scholar] [CrossRef] [PubMed]
- Liu, T.; Wei, Q.; Jin, J.; Luo, Q.; Liu, Y.; Yang, Y.; Cheng, C.; Li, L.; Pi, J.; Si, Y.; et al. The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation. Nucleic Acids Res. 2020, 48, 3816–3831. [Google Scholar] [CrossRef]
- Hao, L.; Wang, J.M.; Liu, B.Q.; Yan, J.; Li, C.; Jiang, J.Y.; Zhao, F.Y.; Qiao, H.Y.; Wang, H.Q. m6A-YTHDF1-mediated TRIM29 upregulation facilitates the stem cell-like phenotype of cisplatin-resistant ovarian cancer cells. Biochim. Biophys. Acta Mol. Cell Res. 2021, 1868, 118878. [Google Scholar] [CrossRef]
- Xu, F.; Li, J.; Ni, M.; Cheng, J.; Zhao, H.; Wang, S.; Zhou, X.; Wu, X. FBW7 suppresses ovarian cancer development by targeting the N(6)-methyladenosine binding protein YTHDF2. Mol. Cancer 2021, 20, 45. [Google Scholar] [CrossRef]
- Li, J.; Wu, L.; Pei, M.; Zhang, Y. YTHDF2, a protein repressed by miR-145, regulates proliferation, apoptosis, and migration in ovarian cancer cells. J. Ovarian Res. 2020, 13, 111. [Google Scholar] [CrossRef]
- Wang, Y.; Chen, Z. Long noncoding RNA UBA6-AS1 inhibits the malignancy of ovarian cancer cells via suppressing the decay of UBA6 mRNA. Bioengineered 2022, 13, 178–189. [Google Scholar] [CrossRef] [PubMed]
- Tatekawa, S.; Tamari, K.; Chijimatsu, R.; Konno, M.; Motooka, D.; Mitsufuji, S.; Akita, H.; Kobayashi, S.; Murakumo, Y.; Doki, Y.; et al. N(6)-methyladenosine methylation-regulated polo-like kinase 1 cell cycle homeostasis as a potential target of radiotherapy in pancreatic adenocarcinoma. Sci. Rep. 2022, 12, 11074. [Google Scholar] [CrossRef] [PubMed]
- Hua, Y.Q.; Zhang, K.; Sheng, J.; Ning, Z.Y.; Li, Y.; Shi, W.D.; Liu, L.M. NUCB1 Suppresses Growth and Shows Additive Effects With Gemcitabine in Pancreatic Ductal Adenocarcinoma via the Unfolded Protein Response. Front. Cell Dev. Biol. 2021, 9, 641836. [Google Scholar] [CrossRef] [PubMed]
- Zhang, J.; Bai, R.; Li, M.; Ye, H.; Wu, C.; Wang, C.; Li, S.; Tan, L.; Mai, D.; Li, G.; et al. Excessive miR-25-3p maturation via N(6)-methyladenosine stimulated by cigarette smoke promotes pancreatic cancer progression. Nat. Commun. 2019, 10, 1858. [Google Scholar] [CrossRef] [PubMed]
- Chen, J.Q.; Tao, Y.P.; Hong, Y.G.; Li, H.F.; Huang, Z.P.; Xu, X.F.; Zheng, H.; Hu, L.K. M(6)A-mediated up-regulation of LncRNA LIFR-AS1 enhances the progression of pancreatic cancer via miRNA-150-5p/ VEGFA/Akt signaling. Cell Cycle 2021, 20, 2507–2518. [Google Scholar] [CrossRef]
- Huang, H.; Li, H.; Pan, R.; Wang, S.; Khan, A.A.; Zhao, Y.; Zhu, H.; Liu, X. Ribosome 18S m(6)A methyltransferase METTL5 promotes pancreatic cancer progression by modulating c-Myc translation. Int. J. Oncol. 2022, 60, 9. [Google Scholar] [CrossRef]
- Zhang, C.; Ou, S.; Zhou, Y.; Liu, P.; Zhang, P.; Li, Z.; Xu, R.; Li, Y. m(6)A Methyltransferase METTL14-Mediated Upregulation of Cytidine Deaminase Promoting Gemcitabine Resistance in Pancreatic Cancer. Front. Oncol. 2021, 11, 696371. [Google Scholar] [CrossRef]
- Wang, M.; Liu, J.; Zhao, Y.; He, R.; Xu, X.; Guo, X.; Li, X.; Xu, S.; Miao, J.; Guo, J.; et al. Upregulation of METTL14 mediates the elevation of PERP mRNA N(6) adenosine methylation promoting the growth and metastasis of pancreatic cancer. Mol. Cancer 2020, 19, 130. [Google Scholar] [CrossRef]
- Chen, S.; Yang, C.; Wang, Z.W.; Hu, J.F.; Pan, J.J.; Liao, C.Y.; Zhang, J.Q.; Chen, J.Z.; Huang, Y.; Huang, L.; et al. CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2 and promotes growth and metastasis of pancreatic cancer. J. Hematol. Oncol. 2021, 14, 60. [Google Scholar] [CrossRef]
- Liu, Y.; Shi, M.; He, X.; Cao, Y.; Liu, P.; Li, F.; Zou, S.; Wen, C.; Zhan, Q.; Xu, Z.; et al. LncRNA-PACERR induces pro-tumour macrophages via interacting with miR-671-3p and m6A-reader IGF2BP2 in pancreatic ductal adenocarcinoma. J. Hematol. Oncol. 2022, 15, 52. [Google Scholar] [CrossRef]
- Xu, X.; Yu, Y.; Zong, K.; Lv, P.; Gu, Y. Up-regulation of IGF2BP2 by multiple mechanisms in pancreatic cancer promotes cancer proliferation by activating the PI3K/Akt signaling pathway. J. Exp. Clin. Cancer Res. 2019, 38, 497. [Google Scholar] [CrossRef]
- Wang, W.; He, Y.; Zhai, L.L.; Chen, L.J.; Yao, L.C.; Wu, L.; Tang, Z.G.; Ning, J.Z. m(6)A RNA demethylase FTO promotes the growth, migration and invasion of pancreatic cancer cells through inhibiting TFPI-2. Epigenetics 2022, 17, 1738–1752. [Google Scholar] [CrossRef] [PubMed]
- Tang, X.; Liu, S.; Chen, D.; Zhao, Z.; Zhou, J. The role of the fat mass and obesity-associated protein in the proliferation of pancreatic cancer cells. Oncol. Lett. 2019, 17, 2473–2478. [Google Scholar] [CrossRef] [Green Version]
- Tan, Z.; Shi, S.; Xu, J.; Liu, X.; Lei, Y.; Zhang, B.; Hua, J.; Meng, Q.; Wang, W.; Yu, X.; et al. RNA N6-methyladenosine demethylase FTO promotes pancreatic cancer progression by inducing the autocrine activity of PDGFC in an m(6)A-YTHDF2-dependent manner. Oncogene 2022, 41, 2860–2872. [Google Scholar] [CrossRef] [PubMed]
- Zeng, J.; Zhang, H.; Tan, Y.; Wang, Z.; Li, Y.; Yang, X. m6A demethylase FTO suppresses pancreatic cancer tumorigenesis by demethylating PJA2 and inhibiting Wnt signaling. Mol. Ther. Nucleic Acids 2021, 25, 277–292. [Google Scholar] [CrossRef]
- Huang, C.; Zhou, S.; Zhang, C.; Jin, Y.; Xu, G.; Zhou, L.; Ding, G.; Pang, T.; Jia, S.; Cao, L. ZC3H13-mediated N6-methyladenosine modification of PHF10 is impaired by fisetin which inhibits the DNA damage response in pancreatic cancer. Cancer Lett. 2022, 530, 16–28. [Google Scholar] [CrossRef]
- Hu, Y.; Tang, J.; Xu, F.; Chen, J.; Zeng, Z.; Han, S.; Wang, F.; Wang, D.; Huang, M.; Zhao, Y.; et al. A reciprocal feedback between N6-methyladenosine reader YTHDF3 and lncRNA DICER1-AS1 promotes glycolysis of pancreatic cancer through inhibiting maturation of miR-5586-5p. J. Exp. Clin. Cancer Res. 2022, 41, 69. [Google Scholar] [CrossRef]
- Deng, J.; Zhang, J.; Ye, Y.; Liu, K.; Zeng, L.; Huang, J.; Pan, L.; Li, M.; Bai, R.; Zhuang, L.; et al. N(6) -methyladenosine-Mediated Upregulation of WTAPP1 Promotes WTAP Translation and Wnt Signaling to Facilitate Pancreatic Cancer Progression. Cancer Res. 2021, 81, 5268–5283. [Google Scholar] [CrossRef]
- Hou, Y.; Zhang, Q.; Pang, W.; Hou, L.; Liang, Y.; Han, X.; Luo, X.; Wang, P.; Zhang, X.; Li, L.; et al. YTHDC1-mediated augmentation of miR-30d in repressing pancreatic tumorigenesis via attenuation of RUNX1-induced transcriptional activation of Warburg effect. Cell Death Differ. 2021, 28, 3105–3124. [Google Scholar] [CrossRef] [PubMed]
- Guo, X.; Li, K.; Jiang, W.; Hu, Y.; Xiao, W.; Huang, Y.; Feng, Y.; Pan, Q.; Wan, R. RNA demethylase ALKBH5 prevents pancreatic cancer progression by posttranscriptional activation of PER1 in an m6A-YTHDF2-dependent manner. Mol. Cancer 2020, 19, 91. [Google Scholar] [CrossRef]
- He, Y.; Hu, H.; Wang, Y.; Yuan, H.; Lu, Z.; Wu, P.; Liu, D.; Tian, L.; Yin, J.; Jiang, K.; et al. ALKBH5 Inhibits Pancreatic Cancer Motility by Decreasing Long Non-Coding RNA KCNK15-AS1 Methylation. Cell. Physiol. Biochem. 2018, 48, 838–846. [Google Scholar] [CrossRef] [PubMed]
- He, Y.; Yue, H.; Cheng, Y.; Ding, Z.; Xu, Z.; Lv, C.; Wang, Z.; Wang, J.; Yin, C.; Hao, H.; et al. ALKBH5-mediated m(6)A demethylation of KCNK15-AS1 inhibits pancreatic cancer progression via regulating KCNK15 and PTEN/AKT signaling. Cell Death Dis. 2021, 12, 1121. [Google Scholar] [CrossRef]
- Huang, R.; Yang, L.; Zhang, Z.; Liu, X.; Fei, Y.; Tong, W.M.; Niu, Y.; Liang, Z. RNA m(6)A Demethylase ALKBH5 Protects Against Pancreatic Ductal Adenocarcinoma via Targeting Regulators of Iron Metabolism. Front. Cell Dev. Biol. 2021, 9, 724282. [Google Scholar] [CrossRef] [PubMed]
- Tang, B.; Yang, Y.; Kang, M.; Wang, Y.; Wang, Y.; Bi, Y.; He, S.; Shimamoto, F. m(6)A demethylase ALKBH5 inhibits pancreatic cancer tumorigenesis by decreasing WIF-1 RNA methylation and mediating Wnt signaling. Mol. Cancer 2020, 19, 3. [Google Scholar] [CrossRef] [PubMed]
- Chang, M.; Wang, Z.; Gao, J.; Yang, C.; Feng, M.; Niu, Y.; Tong, W.M.; Bao, X.; Wang, R. METTL3-mediated RNA m6A Hypermethylation Promotes Tumorigenesis and GH Secretion of Pituitary Somatotroph Adenomas. J. Clin. Endocrinol. Metab. 2022, 107, 136–149. [Google Scholar] [CrossRef]
- Thiery, J.P.; Acloque, H.; Huang, R.Y.; Nieto, M.A. Epithelial-mesenchymal transitions in development and disease. Cell 2009, 139, 871–890. [Google Scholar] [CrossRef]
- Mani, S.A.; Guo, W.; Liao, M.J.; Eaton, E.N.; Ayyanan, A.; Zhou, A.Y.; Brooks, M.; Reinhard, F.; Zhang, C.C.; Shipitsin, M.; et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008, 133, 704–715. [Google Scholar] [CrossRef]
- Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674. [Google Scholar] [CrossRef]
- Schlumberger, M.; Brose, M.; Elisei, R.; Leboulleux, S.; Luster, M.; Pitoia, F.; Pacini, F. Definition and management of radioactive iodine-refractory differentiated thyroid cancer. Lancet Diabetes Endocrinol. 2014, 2, 356–358. [Google Scholar] [CrossRef] [PubMed]
- Cao, J.; Mu, Q.; Huang, H. The Roles of Insulin-Like Growth Factor 2 mRNA-Binding Protein 2 in Cancer and Cancer Stem Cells. Stem Cells Int. 2018, 2018, 4217259. [Google Scholar] [CrossRef]
- Su, T.S.; Liu, W.Y.; Han, S.H.; Jansen, M.; Yang-Fen, T.L.; P’Eng, F.K.; Chou, C.K. Transcripts of the insulin-like growth factors I and II in human hepatoma. Cancer Res. 1989, 49, 1773–1777. [Google Scholar]
- Cleynen, I.; Brants, J.R.; Peeters, K.; Deckers, R.; Debiec-Rychter, M.; Sciot, R.; Van de Ven, W.J.; Petit, M.M. HMGA2 regulates transcription of the Imp2 gene via an intronic regulatory element in cooperation with nuclear factor-kappaB. Mol. Cancer Res. 2007, 5, 363–372. [Google Scholar] [CrossRef]
- Janiszewska, M.; Suvà, M.L.; Riggi, N.; Houtkooper, R.H.; Auwerx, J.; Clément-Schatlo, V.; Radovanovic, I.; Rheinbay, E.; Provero, P.; Stamenkovic, I. Imp2 controls oxidative phosphorylation and is crucial for preserving glioblastoma cancer stem cells. Genes Dev. 2012, 26, 1926–1944. [Google Scholar] [CrossRef]
- Stewart, C.; Ralyea, C.; Lockwood, S. Ovarian Cancer: An Integrated Review. Semin. Oncol. Nurs. 2019, 35, 151–156. [Google Scholar] [CrossRef]
- Luvero, D.; Plotti, F.; Aloisia, A.; Montera, R.; Terranova, C.; Carlo, D.C.N.; Scaletta, G.; Lopez, S.; Miranda, A.; Capriglione, S.; et al. Ovarian cancer relapse: From the latest scientific evidence to the best practice. Crit. Rev. Oncol. Hematol. 2019, 140, 28–38. [Google Scholar] [CrossRef]
- Kleinschmidt, E.G.; Miller, N.; Ozmadenci, D.; Tancioni, I.; Osterman, C.D.; Barrie, A.M.; Taylor, K.N.; Ye, A.; Jiang, S.; Connolly, D.C.; et al. Rgnef promotes ovarian tumor progression and confers protection from oxidative stress. Oncogene 2019, 38, 6323–6337. [Google Scholar] [CrossRef] [PubMed]
- Bast, R.J.; Hennessy, B.; Mills, G.B. The biology of ovarian cancer: New opportunities for translation. Nat. Rev. Cancer 2009, 9, 415–428. [Google Scholar] [CrossRef] [PubMed]
- Henderson, J.T.; Webber, E.M.; Sawaya, G.F. Screening for Ovarian Cancer: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA 2018, 319, 595–606. [Google Scholar] [CrossRef]
- Furuya, M. Ovarian cancer stroma: Pathophysiology and the roles in cancer development. Cancers 2012, 4, 701–724. [Google Scholar] [CrossRef]
- Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2019. Cancer J. Clin. 2019, 69, 7–34. [Google Scholar] [CrossRef]
- Bitler, B.G.; Watson, Z.L.; Wheeler, L.J.; Behbakht, K. PARP inhibitors: Clinical utility and possibilities of overcoming resistance. Gynecol. Oncol. 2017, 147, 695–704. [Google Scholar] [CrossRef] [PubMed]
- Kuczynski, E.A.; Sargent, D.J.; Grothey, A.; Kerbel, R.S. Drug rechallenge and treatment beyond progression--implications for drug resistance. Nat. Rev. Clin. Oncol. 2013, 10, 571–587. [Google Scholar] [CrossRef] [PubMed]
- Nieman, K.M.; Kenny, H.A.; Penicka, C.V.; Ladanyi, A.; Buell-Gutbrod, R.; Zillhardt, M.R.; Romero, I.L.; Carey, M.S.; Mills, G.B.; Hotamisligil, G.S.; et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat. Med. 2011, 17, 1498–1503. [Google Scholar] [CrossRef] [PubMed]
- Liu, W.; Wang, W.; Wang, X.; Xu, C.; Zhang, N.; Di, W. Cisplatin-stimulated macrophages promote ovarian cancer migration via the CCL20-CCR6 axis. Cancer Lett. 2020, 472, 59–69. [Google Scholar] [CrossRef]
- Cao, L.; Shao, M.; Schilder, J.; Guise, T.; Mohammad, K.S.; Matei, D. Tissue transglutaminase links TGF-β, epithelial to mesenchymal transition and a stem cell phenotype in ovarian cancer. Oncogene 2012, 31, 2521–2534. [Google Scholar] [CrossRef]
- Takai, M.; Terai, Y.; Kawaguchi, H.; Ashihara, K.; Fujiwara, S.; Tanaka, T.; Tsunetoh, S.; Tanaka, Y.; Sasaki, H.; Kanemura, M.; et al. The EMT (epithelial-mesenchymal-transition)-related protein expression indicates the metastatic status and prognosis in patients with ovarian cancer. J. Ovarian Res. 2014, 7, 76. [Google Scholar] [CrossRef] [PubMed]
- Mitra, R.; Chen, X.; Greenawalt, E.J.; Maulik, U.; Jiang, W.; Zhao, Z.; Eischen, C.M. Decoding critical long non-coding RNA in ovarian cancer epithelial-to-mesenchymal transition. Nat. Commun. 2017, 8, 1604. [Google Scholar] [CrossRef]
- Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer J. Clin. 2018, 68, 394–424. [Google Scholar] [CrossRef] [PubMed]
- Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2020. Cancer J. Clin. 2020, 70, 7–30. [Google Scholar] [CrossRef]
- Chandana, S.; Babiker, H.M.; Mahadevan, D. Therapeutic trends in pancreatic ductal adenocarcinoma (PDAC). Expert Opin. Investig. Drugs 2019, 28, 161–177. [Google Scholar] [CrossRef]
- Kamisawa, T.; Wood, L.D.; Itoi, T.; Takaori, K. Pancreatic cancer. Lancet 2016, 388, 73–85. [Google Scholar] [CrossRef]
- Orth, M.; Metzger, P.; Gerum, S.; Mayerle, J.; Schneider, G.; Belka, C.; Schnurr, M.; Lauber, K. Pancreatic ductal adenocarcinoma: Biological hallmarks, current status, and future perspectives of combined modality treatment approaches. Radiat. Ther. 2019, 14, 141. [Google Scholar] [CrossRef] [PubMed]
- Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer Statistics, 2021. Cancer J. Clin. 2021, 71, 7–33. [Google Scholar] [CrossRef] [PubMed]
- Connor, A.A.; Gallinger, S. Pancreatic cancer evolution and heterogeneity: Integrating omics and clinical data. Nat. Rev. Cancer 2022, 22, 131–142. [Google Scholar] [CrossRef]
- Mizrahi, J.D.; Surana, R.; Valle, J.W.; Shroff, R.T. Pancreatic cancer. Lancet 2020, 395, 2008–2020. [Google Scholar] [CrossRef]
- Ihrie, R.A.; Marques, M.R.; Nguyen, B.T.; Horner, J.S.; Papazoglu, C.; Bronson, R.T.; Mills, A.A.; Attardi, L.D. Perp is a p63-regulated gene essential for epithelial integrity. Cell 2005, 120, 843–856. [Google Scholar] [CrossRef]
- Awais, R.; Spiller, D.G.; White, M.R.; Paraoan, L. p63 is required beside p53 for PERP-mediated apoptosis in uveal melanoma. Br. J. Cancer 2016, 115, 983–992. [Google Scholar] [CrossRef]
- Yeh, P.J.; Chen, J.W. Pituitary tumors: Surgical and medical management. J. Surg. Oncol. 1997, 6, 67–92. [Google Scholar] [CrossRef] [PubMed]
- Dorton, A.M. The pituitary gland: Embryology, physiology, and pathophysiology. Neonatal Netw. 2000, 19, 9–17. [Google Scholar] [CrossRef]
- Ostrom, Q.T.; Gittleman, H.; Liao, P.; Rouse, C.; Chen, Y.; Dowling, J.; Wolinsky, Y.; Kruchko, C.; Barnholtz-Sloan, J. CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2007–2011. Neuro-Oncol. 2014, 16 (Suppl. S4), iv1–iv63. [Google Scholar] [CrossRef]
- Chen, Y.; Wang, C.D.; Su, Z.P.; Chen, Y.X.; Cai, L.; Zhuge, Q.C.; Wu, Z.B. Natural history of postoperative nonfunctioning pituitary adenomas: A systematic review and meta-analysis. Neuroendocrinology 2012, 96, 333–342. [Google Scholar] [CrossRef]
- Ezzat, S.; Asa, S.L.; Couldwell, W.T.; Barr, C.E.; Dodge, W.E.; Vance, M.L.; McCutcheon, I.E. The prevalence of pituitary adenomas: A systematic review. Am. Cancer Soc. 2004, 101, 613–619. [Google Scholar] [CrossRef] [PubMed]
- Melmed, S. Pituitary-Tumor Endocrinopathies. N. Engl. J. Med. 2020, 382, 937–950. [Google Scholar] [CrossRef] [PubMed]
- Hansen, T.M.; Batra, S.; Lim, M.; Gallia, G.L.; Burger, P.C.; Salvatori, R.; Wand, G.; Quinones-Hinojosa, A.; Kleinberg, L.; Redmond, K.J. Invasive adenoma and pituitary carcinoma: A SEER database analysis. Neurosurg. Rev. 2014, 37, 279–286. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lucas, J.W.; Bodach, M.E.; Tumialan, L.M.; Oyesiku, N.M.; Patil, C.G.; Litvack, Z.; Aghi, M.K.; Zada, G. Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline on Primary Management of Patients With Nonfunctioning Pituitary Adenomas. Neurosurgery 2016, 79, E533–E535. [Google Scholar] [CrossRef]
- Karki, M.; Sun, J.; Yadav, C.P.; Zhao, B. Large and giant pituitary adenoma resection by microscopic trans-sphenoidal surgery: Surgical outcomes and complications in 123 consecutive patients. J. Clin. Neurosci. 2017, 44, 310–314. [Google Scholar] [CrossRef]
- Salomon, M.P.; Wang, X.; Marzese, D.M.; Hsu, S.C.; Nelson, N.; Zhang, X.; Matsuba, C.; Takasumi, Y.; Ballesteros-Merino, C.; Fox, B.A.; et al. The Epigenomic Landscape of Pituitary Adenomas Reveals Specific Alterations and Differentiates Among Acromegaly, Cushing’s Disease and Endocrine-Inactive Subtypes. Clin. Cancer Res. 2018, 24, 4126–4136. [Google Scholar] [CrossRef]
- Reddy, R.; Cudlip, S.; Byrne, J.V.; Karavitaki, N.; Wass, J.A. Can we ever stop imaging in surgically treated and radiotherapy-naive patients with non-functioning pituitary adenoma? Eur. J. Endocrinol. 2011, 165, 739–744. [Google Scholar] [CrossRef]
- Tzelepis, K.; Rausch, O.; Kouzarides, T. RNA-modifying enzymes and their function in a chromatin context. Nat. Struct. Mol. Biol. 2019, 26, 858–862. [Google Scholar] [CrossRef]
- Yankova, E.; Blackaby, W.; Albertella, M.; Rak, J.; De Braekeleer, E.; Tsagkogeorga, G.; Pilka, E.S.; Aspris, D.; Leggate, D.; Hendrick, A.G.; et al. Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia. Nature 2021, 593, 597–601. [Google Scholar] [CrossRef]
- Burgess, H.M.; Depledge, D.P.; Thompson, L.; Srinivas, K.P.; Grande, R.C.; Vink, E.I.; Abebe, J.S.; Blackaby, W.P.; Hendrick, A.; Albertella, M.R.; et al. Targeting the m(6)A RNA modification pathway blocks SARS-CoV-2 and HCoV-OC43 replication. Genes Dev. 2021, 35, 1005–1019. [Google Scholar] [CrossRef]
Endocrine Cancer | m6A Component | Function | Role in Disease | Regulation | Related Target | Mechanism | Year | Ref |
---|---|---|---|---|---|---|---|---|
Thyroid cancer | METTL3 | Writer | Anti-oncogene | Upregulation | YTHDF1/STEAP2 | METTL3 stabilized STEAP2 mRNA and regulated STEAP2 expression positively through YTHDF1-mediated m(6)A modification. METTL3–STEAP2 axis functions as an inhibitr in PTC by suppressing epithelial-mesenchymal transition and the Hedgehog signaling pathway. | 2022 | [68] |
METTL3 | Writer | Anti-oncogene | Downregulation | YTHDF2/c-Rel and RelA | METTL3 played a pivotal tumor-suppressor role in PTC carcinogenesis through c-Rel and RelA inactivation of the nuclear factor κB (NF-κB) pathway by cooperating with YTHDF2 and altered TAN infiltration to regulate tumor growth | 2021 | [69] | |
METTL3 | Writer | Oncogene | Upregulation | IGF2BP2/TCF1 | Upregulated m6A methyltransferase METTL3 recruits IGFBP2 and promotes the progression of thyroid carcinoma through m(6)A methylation on TCF1 | 2020 | [70] | |
METTL3 | Writer | Oncogene | Upregulation | miR-222-3p/STK4 | METTL3 stimulated miR-222-3p expression by mediating the m6A modification of pri-miR-222-3p. miR-222-3p targeted and inversely regulated serine/threonine stress kinase 4 (STK4), thereby increasing the malignant behaviors of TC cells | 2022 | [71] | |
FTO | Eraser | Anti-oncogene | Downregulation | APOE | FTO inhibited expression of APOE through IGF2BP2-mediated m(6)A modification and may inhibit glycolytic metabolism in PTC by modulating IL-6/JAK2/STAT3 signaling pathway. | 2022 | [72] | |
FTO | Eraser | Anti-oncogene | Downregulation | SLC7A11 | FTO functions as a tumor suppressor gene in PTC and is able to inhibit the occurrence of PTC by downregulating SLC7A11 in m6A independently. | 2022 | [73] | |
IGF2BP2 | Reader | Oncogene | Upregulation | ERBB2 | IGF2BP2 bound to the N6-methyladenosine-binding site in the coding sequence of ERBB2 mRNA, yielding an increased ERBB2 translation efficacy. Inhibition of ERBB2 and IGF2BP2 rescued the PTCSR cells from acquired dedifferentiation. | 2022 | [74] | |
IGF2BP2 | Reader | Oncogene | Upregulation | RUNX2 | IGF2BP2 bound to the m6A modification site of runt-related transcription factor 2 (RUNX2) 3’-UTR and enhanced the RUNX2 mRNA stability. Moreover, RUNX2 could bind to the promoter region of NIS to block the differentiation of RR-PTC | 2022 | [75] | |
IGF2BP2 | Reader | Oncogene | Upregulation | miR-204/MALAT1 | MALAT1 contributes to TC progression through the upregulation of IGF2BP2 by binding to miR-204. | 2021 | [76] | |
IGF2BP2 | Reader | Oncogene | Upregulation | HAGLR | IGF2BP2 loss inhibited cell proliferation, migration and invasion, and induced cell apoptosis and cell cycle arrest by down-regulating HAGLR expression in an m6A-dependent manner in TC cells | 2021 | [77] | |
Ovarian cancer | METTL3 | Writer | Oncogene | Upregulation | miR-126-5p/PTEN | Knockdown of METTL3 inhibited the effect of miR-126-5p to upregulate PTEN, and thus prevents PI3K/Akt/mTOR pathway activation, thereby suppressing the development of ovarian cancer. | 2021 | [78] |
METTL3 | Writer | Oncogene | Upregulation | AXL | METTL3 promoted EMT by upregulating the receptor tyrosine kinase AXL, thereby facilitating metastasis of ovarian cancer. | 2018 | [79] | |
METTL14 | Writer | Anti-oncogene | Downregulation | TROAP | METTL14 overexpression decreased ovarian cancer proliferation by inhibition of TROAP expression via an m(6)A RNA methylation-dependent mechanism. | 2022 | [80] | |
WTAP | Writer | Oncogene | Upregulation | miR-200/HK2 | HIF-1α could positively regulate increased expression of WTAP under hypoxia; WTAP interacts with DGCR8 (a crucial chip protein) to regulate the expression of miR-200 in an m6A-dependent way; key glycolysis enzyme HK2 could be positively regulated by miR-200, which significantly affected the intracellular Warburg effect. | 2022 | [81] | |
ALKBH5 | Eraser | Oncogene | Upregulation | HOXA10/JAK2 | HOXA10 formed a loop with ALKBH5 and was found to be the upstream transcription factor of ALKBH5. JAK2 is the m6A-modified gene targeted by ALKBH5. The JAK2/STAT3 signaling pathway was activated by overexpression of the ALKBH5-HOXA10 loop, resulting in EOC chemoresistance. | 2021 | [82] | |
ALKBH5 | Eraser | Oncogene | Upregulation | NANOG | TLR4 up-regulated ALKBH5 expression via activating the NF-κB pathway. NANOG served as a target in ALKBH5-mediated m6A modification. NANOG expression increased after mRNA demethylation, consequently enhancing the aggressiveness of ovarian cancer cells. | 2020 | [83] | |
FTO | Eraser | Anti-oncogene | Downregulation | PDE1C and PDE4B | By reducing m(6)A levels at the 3’UTR and the mRNA stability of PDE1C and PDE4B, FTO augmented second messenger 3’, 5’-cAMP signaling and suppressed stemness features of ovarian cancer cells. | 2020 | [84] | |
YTHDF1 | Reader | Oncogene | Upregulation | EIF3C | YTHDF1 augments the translation of EIF3C in an m6A-dependent manner by binding to m6A-modified EIF3C mRNA and concomitantly promotes the overall translational output, thereby facilitating tumorigenesis and metastasis of ovarian cancer. | 2020 | [85] | |
YTHDF1 | Reader | Oncogene | Upregulation | TRIM29 | TRIM29 could act as an oncogene to enhance the CSC-like characteristics of the cisplatin-resistant ovarian cancer cells. In addition, recruitment of YTHDF1 to m6A-modified TRIM29 was involved in promoting TRIM29 translation in the cisplatin-resistant ovarian cancer cells. | 2021 | [86] | |
YTHDF2 | Reader | Oncogene | Upregulation | BMF | Ectopic FBW7 inhibits ovarian cancer cell survival and proliferation. FBW7 counteracts the tumor-promoting effect of YTHDF2 by inducing proteasomal degradation of the latter in ovarian cancer. Furthermore, YTHDF2 globally regulates the turnover of m(6)A-modified mRNAs, including the pro-apoptotic gene BMF. | 2021 | [87] | |
YTHDF2 | Reader | Oncogene | Downregulation | miR-145 | YTHDF2 was the direct target gene of miR-145. A crucial crosstalk occurred between miR-145 and YTHDF2 via a double-negative feedback loop. YTHDF2 and miR-145 were involved in the progression of EOC by indirectly modulating m6A levels. | 2020 | [88] | |
IGF2BP1 | Reader | Anti-oncogene | Upregulation | UBA6 | UBA6-AS1 increased the m6A methylation of UBA6 mRNA via recruiting RBM15. IGF2BP1 as the m6A reader protein enhanced the stability of UBA6 mRNA. | 2022 | [89] | |
pancreatic cancer | METTL3 | Writer | Anti-oncogene | Upregulation | IGF2BP2/PLK1 | IGF2BP2 binds to m6A of PLK1 3’ untranslated region and is involved in upregulating PLK1 expression and that demethylation of this site activates the ataxia telangiectasia and Rad3-related protein pathway by replicating stress and increasing mitotic catastrophe, resulting in increased radiosensitivity. | 2022 | [90] |
METTL3 | Writer | Oncogene | Downregulation | NUCB1 | METTL3-mediated m(6)A modification on NUCB1 5’UTR via YTHDF2 as a mechanism for NUCB1 downregulation in PDAC. By controlling ATF6 activity, NUCB1 overexpression suppressed GEM-induced UPR and autophagy. | 2021 | [91] | |
METTL3 | Writer | Oncogene | Upregulation | miR-25-3p | Cigarette smoke condensate (CSC) caused the hypomethylation of the METTL3 promoter. Overexpressed METTL3 catalyzed the maturate of primary miR-25, which is mediated by NKAP. Mature miR-25, miR-25-3p, suppresses PHLPP2, resulting in the activation of oncogenic AKT-p70S6K signaling, which provokes malignant phenotypes of pancreatic cancer cells. | 2019 | [92] | |
METTL3 | Writer | Oncogene | Upregulation | LIFR-AS1 | METTL3 induced m(6)A hyper-methylation on the 3’ UTR of LIFR-AS1 to enhance its mRNA stability and LIFR-AS1 could directly interact with miR-150-5p, thereby indirectly upregulating VEGFA expressions within cells and impact VEGFA/PI3K/Akt signaling. | 2021 | [93] | |
METTL5 | Writer | Oncogene | Upregulation | c-Myc | m(6)A modifications at the 5’ untranslated region (5’UTR) and coding DNA sequence region (near the 5’UTR) of c-Myc mRNA played a critical role in the specific translation regulation by METTL5. In addition, METTL5 and its cofactor tRNA methyltransferase activator subunit 11-2 synergistically promote pancreatic cancer progression. | 2022 | [94] | |
METTL14 | Writer | Oncogene | Upregulation | CDA | The transcriptional factor p65 targeted the promoter region of METTL14 and upregulated its expression, which then increased the expression of CDA, an enzyme-inactivate gemcitabine. Furthermore, depletion of METTL14 rescue the response of the resistance cell to gemcitabine. | 2021 | [95] | |
METTL14 | Writer | Oncogene | Downregulation | PERP | METTL14 direct targeting of the downstream PERP mRNA (p53 effector related to PMP-22) in an m(6)A-dependent manner. Methylation of the target adenosine lead to increased PERP mRNA turnover, thus decreasing PERP (mRNA and protein) levels in pancreatic cancer cells, promoting the growth and metastasis of pancreatic cancer. | 2020 | [96] | |
METTL14 | Writer | Oncogene | Upregulation | CLK1/SRSF5 | CLK1 enhanced phosphorylation on SRSF5(250-Ser), which inhibited METTL14(exon10) skipping while promoted cyclin L2(exon6.3) skipping. In addition, aberrant METTL14(exon10) skipping enhanced the N6-methyladenosine modification level and metastasis, while aberrant cyclin L2(exon6.3) promoted proliferation of PDAC cells. | 2021 | [97] | |
IGF2BP2 | Reader | Oncogene | Upregulation | lncPACERR/miR-671-3p | LncRNA-PACERR activate KLF12/p-AKT/c-myc pathway by binding to miR-671-3p. LncRNA-PACERR which binds to IGF2BP2 acts in an m6A-dependent manner to enhance the stability of KLF12 and c-myc in cytoplasm. In addition, the promoter of LncRNA-PACERR was a target of KLF12 and LncRNA-PACERR recruited EP300 to increase the acetylation of histone by interacting with KLF12 in nucleus. | 2022 | [98] | |
IGF2BP2 | Reader | Oncogene | Downregulation | miR-141 | IGF2BP2 is a direct target of miR-141. A negative correlation between IGF2BP2 mRNA expression and the expression of miR-141. Moreover, upregulating IGF2BP2 expression promotes pancreatic cancer cell growth by activating the PI3K/Akt signaling pathway in vitro and in vivo. | 2019 | [99] | |
FTO | Eraser | Oncogene | Downregulation | YTHDF1/TFPI-2 | FTO promotes the progression of PC through reducing m(6)A/YTHDF1 mediated TFPI-2 mRNA stability. | 2022 | [100] | |
FTO | Eraser | Oncogene | Upregulation | MYC and bHLH | FTO interact with MYC proto-oncogene, bHLH transcription factor and enhance its stability by decreasing its m(6)A level, which promotes growth and metastasis and regulates PDAC cells. | 2019 | [101] | |
FTO | Eraser | Oncogene | Upregulation | YTHDF2/PDGFC | FTO directly targets PDGFC and stabilizes its mRNA expression in an m(6)A-YTHDF2-dependent manner. PDGFC upregulation led to reactivation of the Akt signaling pathway, promoting PC cell growth. | 2022 | [102] | |
FTO | Eraser | Anti-oncogene | Upregulation | YTHDF2/PJA2 | FTO demethylated the m6A modification of praja ring finger ubiquitin ligase 2 (PJA2), thereby reducing its mRNA decay, suppressing Wnt signaling, and ultimately restraining the proliferation, invasion, and metastasis of pancreatic cancer cells. | 2021 | [103] | |
YTHDF1 | Reader | Anti-oncogene | Downregulation | PHF10 | PHF10 was found and involved in the DNA damage response. PHF10 loss-of-function resulted in elevated recruitment of γH2AX, RAD51, and 53BP1 to DSB sites and decreased HR repair efficiency. Moreover, ZC3H13 knockdown downregulated the m(6)A methylation of PHF10 and decreased PHF10 translation in a YTHDF1-dependent manner. | 2022 | [104] | |
YTHDF3 | Reader | Oncogene | Downregulation | DICER1-AS1 | YTHDF3 was a critical target for miR-5586-5p, forming negative feedback with DICER1-AS1. The negative feedback of YTHDF3 and glycolytic lncRNA DICER1-AS1 is involved in glycolysis and tumorigenesis of PC. | 2022 | [105] | |
WTAP | Writer | Oncogene | Upregulation | WTAPP1 | m6A modification stabilized WTAPP1 RNA via CNBP, resulting in increased levels of WTAPP1 RNA in PDAC cells. Excessive WTAPP1 RNA bound its protein-coding counterpart WTAP mRNA and recruited more EIF3 translation initiation complexes to promote WTAP translation. Increased WTAP protein enhanced the activation of Wnt signaling and provoked the malignant phenotypes of PDAC. | 2021 | [106] | |
YTHDC1 | Reader | Anti-oncogene | Upregulation | miR-30d/RUNX1 | YTHDC1 facilitated the biogenesis of mature miR-30d via m(6)A-mediated regulation of mRNA stability. Then, miR-30d inhibited aerobic glycolysis through regulating SLC2A1 and HK1 expression by directly targeting the transcription factor RUNX1, which bound to the promoters of the SLC2A1 and HK1 genes. | 2021 | [107] | |
ALKBH5 | Eraser | Anti-oncogene | Upregulation | YTHDF2/PER1 | ALKBH5 post-transcriptionally activated PER1 by m6A demethylation in an m6A-YTHDF2-dependent manner. PER1 upregulation led to the reactivation of ATM-CHK2-P53/CDC25C signalling, which inhibited cell growth. P53-induced activation of ALKBH5 transcription acted as a feedback loop regulating the m6A modifications in PC. | 2020 | [108] | |
ALKBH5 | Eraser | Anti-oncogene | Upregulation | KCNK15-AS1 | ALKBH5 was downregulated in cancer cells, which can demethylate KCNK15-AS1 and regulate KCNK15-AS1-mediated cell motility to inhibit pancreatic cancer motility. | 2018 | [109] | |
ALKBH5 | Eraser | Anti-oncogene | Upregulation | KCNK15-AS1 | ALKBH5 was verified to induce m(6)A demethylation of KCNK15-AS1 to mediate KCNK15-AS1 upregulation. KCNK15-AS1 combined with KCNK15 5’UTR to inhibit KCNK15 translation. Moreover, KCNK15-AS1 recruited MDM2 to promote REST ubiquitination, thus transcriptionally upregulating PTEN to inactivate AKT pathway. | 2021 | [110] | |
ALKBH5 | Eraser | Anti-oncogene | Downregulation | IRP2 and SNAI1 | Owing to FBXL5-mediated degradation, ALKBH5 overexpression incurred a significant reduction in iron-regulatory protein IRP2 and the modulator of EMT SNAI1. ALKBH5 overexpression led to a significant reduction in intracellular iron levels as well as cell migratory and invasive abilities. | 2021 | [111] | |
ALKBH5 | Eraser | Anti-oncogene | Downregulation | WIF-1 | Silencing ALKBH5 is correlated with WIF-1 transactivation and mediation of the Wnt pathway and increases PDAC cell proliferation, migration, and invasion. | 2020 | [112] | |
Pituitary Somatotroph Adenomas | METTL3 | Writer | Oncogene | Upregulation | GNAS and GADD45γ | m6A methyltransferase METTL3 promotes tumor growth and hormone secretion by increasing expression of GNAS and GADD45γ in a m6A-dependent manner. | 2022 | [113] |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Ji, X.; Wang, Z.; Sun, W.; Zhang, H. The Emerging Role of m6A Modification in Endocrine Cancer. Cancers 2023, 15, 1033. https://doi.org/10.3390/cancers15041033
Ji X, Wang Z, Sun W, Zhang H. The Emerging Role of m6A Modification in Endocrine Cancer. Cancers. 2023; 15(4):1033. https://doi.org/10.3390/cancers15041033
Chicago/Turabian StyleJi, Xiaoyu, Zhiyuan Wang, Wei Sun, and Hao Zhang. 2023. "The Emerging Role of m6A Modification in Endocrine Cancer" Cancers 15, no. 4: 1033. https://doi.org/10.3390/cancers15041033