Editorial

2 pages, 165 KiB

Open AccessEditorial

by Hiroaki Taniguchi

Int. J. Mol. Sci. 2023, 24(24), 17275; https://doi.org/10.3390/ijms242417275 - 08 Dec 2023

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Liver cancer, specifically hepatocellular carcinoma (HCC), is a major global health concern due to its high prevalence in many countries [...] Full article

(This article belongs to the Special Issue Liver Cancer 2.0)

Research

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14 pages, 3900 KiB

Open AccessArticle

Genetic Ablation of LAT1 Inhibits Growth of Liver Cancer Cells and Downregulates mTORC1 Signaling

by Sun-Yee Kim, Qunxiang Ong, Yilie Liao, Zhaobing Ding, Alicia Qian Ler Tan, Ler Ting Rachel Lim, Hui Min Tan, Siew Lan Lim, Qian Yi Lee and Weiping Han

Int. J. Mol. Sci. 2023, 24(11), 9171; https://doi.org/10.3390/ijms24119171 - 24 May 2023

Viewed by 1547

Abstract

Through a comprehensive analysis of the gene expression and dependency in HCC patients and cell lines, LAT1 was identified as the top amino acid transporter candidate supporting HCC tumorigenesis. To assess the suitability of LAT1 as a HCC therapeutic target, we used CRISPR/Cas9 [...] Read more.

Through a comprehensive analysis of the gene expression and dependency in HCC patients and cell lines, LAT1 was identified as the top amino acid transporter candidate supporting HCC tumorigenesis. To assess the suitability of LAT1 as a HCC therapeutic target, we used CRISPR/Cas9 to knockout (KO) LAT1 in the epithelial HCC cell line, Huh7. Knockout of LAT1 diminished its branched chain amino acid (BCAA) transport activity and significantly reduced cell proliferation in Huh7. Consistent with in vitro studies, LAT1 ablation led to suppression of tumor growth in a xenograft model. To elucidate the mechanism underlying the observed inhibition of cell proliferation upon LAT1 KO, we performed RNA-sequencing analysis and investigated the changes in the mTORC1 signaling pathway. LAT1 ablation resulted in a notable reduction in phosphorylation of p70S6K, a downstream target of mTORC1, as well as its substrate S6RP. This reduced cell proliferation and mTORC1 activity were rescued when LAT1 was overexpressed. These findings imply an essential role of LAT1 for maintenance of tumor cell growth and additional therapeutic angles against liver cancer. Full article

(This article belongs to the Special Issue Liver Cancer 2.0)

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15 pages, 1530 KiB

Open AccessArticle

Multiparametric Dynamic Ultrasound Approach for Differential Diagnosis of Primary Liver Tumors

by Maria Elena Ainora, Lucia Cerrito, Antonio Liguori, Irene Mignini, Angela De Luca, Linda Galasso, Matteo Garcovich, Laura Riccardi, Francesca Ponziani, Francesco Santopaolo, Maurizio Pompili, Antonio Gasbarrini and Maria Assunta Zocco

Int. J. Mol. Sci. 2023, 24(10), 8548; https://doi.org/10.3390/ijms24108548 - 10 May 2023

Cited by 3 | Viewed by 1475

Abstract

A correct differentiation between hepatocellular carcinoma (HCC) and intracellular cholangiocarcinoma (ICC) is essential for clinical management and prognostic prediction. However, non-invasive differential diagnosis between HCC and ICC remains highly challenging. Dynamic contrast-enhanced ultrasound (D-CEUS) with standardized software is a valuable tool in the [...] Read more.

A correct differentiation between hepatocellular carcinoma (HCC) and intracellular cholangiocarcinoma (ICC) is essential for clinical management and prognostic prediction. However, non-invasive differential diagnosis between HCC and ICC remains highly challenging. Dynamic contrast-enhanced ultrasound (D-CEUS) with standardized software is a valuable tool in the diagnostic approach to focal liver lesions and could improve accuracy in the evaluation of tumor perfusion. Moreover, the measurement of tissue stiffness could add more information concerning tumoral environment. To explore the diagnostic performance of multiparametric ultrasound (MP-US) in differentiating ICC from HCC. Our secondary aim was to develop an US score for distinguishing ICC and HCC. Between January 2021 and September 2022 consecutive patients with histologically confirmed HCC and ICC were enrolled in this prospective monocentric study. A complete US evaluation including B mode, D-CEUS and shear wave elastography (SWE) was performed in all patients and the corresponding features were compared between the tumor entities. For better inter-individual comparability, the blood volume-related D-CEUS parameters were analyzed as a ratio between lesions and surrounding liver parenchyma. Univariate and multivariate regression analysis was performed to select the most useful independent variables for the differential diagnosis between HCC and ICC and to establish an US score for non-invasive diagnosis. Finally, the diagnostic performance of the score was evaluated by receiver operating characteristic (ROC) curve analysis. A total of 82 patients (mean age ± SD, 68 ± 11 years, 55 men) were enrolled, including 44 ICC and 38 HCC. No statistically significant differences in basal US features were found between HCC and ICC. Concerning D-CEUS, blood volume parameters (peak intensity, PE; area under the curve, AUC; and wash-in rate, WiR) showed significantly higher values in the HCC group, but PE was the only independent feature associated with HCC diagnosis at multivariate analysis (p = 0.02). The other two independent predictors of histological diagnosis were liver cirrhosis (p < 0.01) and SWE (p = 0.01). A score based on those variables was highly accurate for the differential diagnosis of primary liver tumors, with an area under the ROC curve of 0.836 and the optimal cut-off values of 0.81 and 0.20 to rule in or rule out ICC respectively. MP-US seems to be a useful tool for non-invasive discrimination between ICC and HCC and could prevent the need for liver biopsy at least in a subgroup of patients. Full article

(This article belongs to the Special Issue Liver Cancer 2.0)

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19 pages, 3690 KiB

Open AccessArticle

Proto-Oncogene FAM50A Can Regulate the Immune Microenvironment and Development of Hepatocellular Carcinoma In Vitro and In Vivo

by Xudong Xie, Li Li, Shuai Tao, Mingsheng Chen, Ling Fei, Qunling Yang, Chenlu Huang and Liang Chen

Int. J. Mol. Sci. 2023, 24(4), 3217; https://doi.org/10.3390/ijms24043217 - 06 Feb 2023

Cited by 2 | Viewed by 1836

Abstract

Hepatocellular carcinoma (HCC) is a vital global health problem. The characteristics are high morbidity, high mortality, difficulty in early diagnosis and insensitivity to chemotherapy. The main therapeutic schemes for treating HCC mainly include Tyrosine kinase inhibitors represented by sorafenib and lenvatinib. In recent [...] Read more.

Hepatocellular carcinoma (HCC) is a vital global health problem. The characteristics are high morbidity, high mortality, difficulty in early diagnosis and insensitivity to chemotherapy. The main therapeutic schemes for treating HCC mainly include Tyrosine kinase inhibitors represented by sorafenib and lenvatinib. In recent years, immunotherapy for HCC has also achieved certain results. However, a great number of patients failed to benefit from systemic therapies. FAM50A belongs to the FAM50 family and can be used as a DNA-binding protein or transcription factor. It may take part in the splicing of RNA precursors. In studies of cancer, FAM50A has been demonstrated to participate in the progression of myeloid breast cancer and chronic lymphocytic leukemia. However, the effect of FAM50A on HCC is still unknown. In this study, we have demonstrated the cancer-promoting effects and diagnostic value of FAM50A in HCC using multiple databases and surgical samples. We identified the role of FAM50A in the tumor immune microenvironment (TIME) and immunotherapy efficacy in HCC. We also proved the effects of FAM50A on the malignancy of HCC in vitro and in vivo. In conclusion, we confirmed that FAM50A is an important proto-oncogene in HCC. FAM50A acts as a diagnostic marker, immunomodulator and therapeutic target for HCC. Full article

(This article belongs to the Special Issue Liver Cancer 2.0)

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23 pages, 7462 KiB

Open AccessArticle

Induction of Apoptosis by Matrine Derivative ZS17 in Human Hepatocellular Carcinoma BEL-7402 and HepG2 Cells through ROS-JNK-P53 Signalling Pathway Activation

by Xiang Wang, Sen Zhang, Keyan Han, Lisheng Wang and Xu Liu

Int. J. Mol. Sci. 2022, 23(24), 15991; https://doi.org/10.3390/ijms232415991 - 15 Dec 2022

Cited by 8 | Viewed by 1678

Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignancies and ranks third among cancer-related deaths worldwide. Using matrine as a lead compound, 12 matrine derivatives were designed and synthesised, and their antiproliferative activities were evaluated in four cancer cell lines. Eight of [...] Read more.

Hepatocellular carcinoma (HCC) is one of the most common malignancies and ranks third among cancer-related deaths worldwide. Using matrine as a lead compound, 12 matrine derivatives were designed and synthesised, and their antiproliferative activities were evaluated in four cancer cell lines. Eight of the twelve compounds showed strong antiproliferative activity, with an IC₅₀ of <10 μM. The compound ZS17 exhibited strong antiproliferative activity in hepatocellular carcinoma cell lines with IC₅₀ values in the range of 3.014–3.388 μM, which was much lower than that of matrine. Furthermore, we explored the role of ZS17 in inducing apoptosis in HCC cells in vitro and in vivo, as well as possible mechanisms involved. ZS17 inhibited the proliferation of BEL-7402 and HepG2 cells in time- and dose-dependent manners. In addition, we found that ZS17 significantly induced apoptosis and ROS (reactive oxygen species) production, promoted JNK phosphorylation, activated p53, and activated the caspase signalling pathway. Furthermore, the antioxidant NAC, JNK inhibitor SP600125, and Si-JNK increased cell viability, re-established cell metastasis, and inhibited ZS17-induced apoptosis. An in vivo antitumour assay demonstrated that ZS17 significantly reduced the number of migrating HepG2 cells in zebrafish embryos and suppressed the growth of HepG2 xenografts in nude mice without any obvious side effects. Our study demonstrated that the ROS-JNK-P53 pathway plays an important role in the destruction of liver tumour cells by ZS17. Thus, ZS17 may represent a promising chemotherapeutic agent for the treatment of HCC patients. Full article

(This article belongs to the Special Issue Liver Cancer 2.0)

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12 pages, 1355 KiB

Open AccessArticle

Genetic Polymorphisms of lncRNA LINC00673 as Predictors of Hepatocellular Carcinoma Progression in an Elderly Population

by Lan-Ting Yuan, Yi-Chieh Yang, Hsiang-Lin Lee, Pei-Chun Shih, Li-Hsin Chen, Chih-Hsin Tang, Lun-Ching Chang, Hsiang-Ling Wang, Shun-Fa Yang and Ming-Hsien Chien

Int. J. Mol. Sci. 2022, 23(21), 12737; https://doi.org/10.3390/ijms232112737 - 22 Oct 2022

Cited by 2 | Viewed by 1346

Abstract

Long noncoding (lnc)RNAs are reported to be key regulators of tumor progression, including hepatocellular carcinoma (HCC). The lncRNA long intergenic noncoding RNA 00673 (LINC00673) was indicated to play an important role in HCC progression, but the impacts of genetic variants (single-nucleotide polymorphisms, SNPs) [...] Read more.

Long noncoding (lnc)RNAs are reported to be key regulators of tumor progression, including hepatocellular carcinoma (HCC). The lncRNA long intergenic noncoding RNA 00673 (LINC00673) was indicated to play an important role in HCC progression, but the impacts of genetic variants (single-nucleotide polymorphisms, SNPs) of LINC00673 on HCC remain unclear. A TaqMan allelic discrimination assay was performed to analyze the genotypes of three tagging SNPs, viz., rs9914618 G > A, rs6501551 A > G, and rs11655237 C > T, of LINC00673 in 783 HCC patients and 1197 healthy subjects. Associations of functional SNPs of LINC00673 with HCC susceptibility and clinicopathologic variables were analyzed by logistic regression models. After stratification by confounding factor, we observed that elderly patients (≥60 years) with the LINC00673 rs9914618 A allele had an increased risk of developing HCC under a codominant model (p = 0.025) and dominant model (p = 0.047). Moreover, elderly patients carrying the GA + AA genotype of rs9914618 exhibited a higher risk of having lymph node metastasis compared to those who were homozygous for the major allele (p = 0.013). Genotype screening of rs9914618 in HCC cell lines showed that cells carrying the AA genotype expressed higher LINC00673 levels compared to the cells carrying the GG genotype. Further analyses of clinical datasets from the Cancer Genome Atlas (TCGA) showed that LINC00673 expressions were upregulated in HCC tissues compared to normal tissues, and were correlated with advanced clinical stages and poorer prognoses. In conclusions, our results suggested that the LINC00673 rs9914618 polymorphism may be a promising HCC biomarker, especially in elderly populations. Full article

(This article belongs to the Special Issue Liver Cancer 2.0)

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13 pages, 2158 KiB

Open AccessArticle

The RNA-Binding Protein ELAVL1 Regulates Hepatitis B Virus Replication and Growth of Hepatocellular Carcinoma Cells

by Hiroaki Kanzaki, Tetsuhiro Chiba, Tatsuya Kaneko, Junjie Ao, Motoyasu Kan, Ryosuke Muroyama, Shingo Nakamoto, Tatsuo Kanda, Hitoshi Maruyama, Jun Kato, Yoh Zen, Ai Kotani, Kazuma Sekiba, Motoyuki Otsuka, Masayuki Ohtsuka and Naoya Kato

Int. J. Mol. Sci. 2022, 23(14), 7878; https://doi.org/10.3390/ijms23147878 - 17 Jul 2022

Cited by 6 | Viewed by 2279

Abstract

Previous RNA immunoprecipitation followed by proteomic approaches successfully demonstrated that Embryonic Lethal, Abnormal Vision, Drosophila-Like 1 (ELAVL1) interacts with hepatitis B virus (HBV)-derived RNAs. Although ELAVL family proteins stabilize AU-rich element (ARE)-containing mRNAs, their role in HBV transcription remains unclear. This study conducted [...] Read more.

Previous RNA immunoprecipitation followed by proteomic approaches successfully demonstrated that Embryonic Lethal, Abnormal Vision, Drosophila-Like 1 (ELAVL1) interacts with hepatitis B virus (HBV)-derived RNAs. Although ELAVL family proteins stabilize AU-rich element (ARE)-containing mRNAs, their role in HBV transcription remains unclear. This study conducted loss-of-function assays of ELAVL1 for inducible HBV-replicating HepAD38 cells and HBx-overexpressed HepG2 cells. In addition, clinicopathological analyses in primary hepatocellular carcinoma (HCC) surgical samples were also conducted. Lentivirus-mediated short hairpin RNA knockdown of ELAVL1 resulted in a decrease in both viral RNA transcription and production of viral proteins, including HBs and HBx, probably due to RNA stabilization by ELAVL1. Cell growth of HepAD38 cells was more significantly impaired in ELAVL1-knockdown than those in the control group, with or without HBV replication, indicating that ELAVL1 is involved in proliferation by factors other than HBV-derived RNAs. Immunohistochemical analyses of 77 paired HCC surgical specimens demonstrated that diffuse ELAVL1 expression was detected more frequently in HCC tissues (61.0%) than in non-tumor tissues (27.3%). In addition, the abundant expression of ELAVL1 tended to affect postoperative recurrence in HBV-related HCC patients. In conclusion, ELAVL1 contributes not only to HBV replication but also to HCC cell growth. It may be a potent therapeutic target for HBV-related HCC treatment. Full article

(This article belongs to the Special Issue Liver Cancer 2.0)

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Review

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14 pages, 872 KiB

Open AccessReview

Chemokines in Primary Liver Cancer

by Monika Zajkowska and Barbara Mroczko

Int. J. Mol. Sci. 2022, 23(16), 8846; https://doi.org/10.3390/ijms23168846 - 09 Aug 2022

Cited by 11 | Viewed by 2691

Abstract

The liver is responsible for extremely important functions in the human body. In the liver’s structure, we distinguish between connective tissue (stroma) and parenchyma, the latter of which is formed from the basic structural and functional units of the liver—hepatocytes. There are many [...] Read more.

The liver is responsible for extremely important functions in the human body. In the liver’s structure, we distinguish between connective tissue (stroma) and parenchyma, the latter of which is formed from the basic structural and functional units of the liver—hepatocytes. There are many factors, that negatively affect the liver cells, contributing to their damage. This may lead to fibrosis, liver failure and, in consequence, primary liver cancer, which is the sixth most commonly diagnosed malignancy and the fourth leading cause of cancer death worldwide. Chemokines are a large family of secreted proteins. Their main role is to direct the recruitment and migration of cells to sites of inflammation or injury. Some authors suggest that these proteins might play a potential role in the development of many malignancies, including primary liver cancer. The aim of this study was to evaluate and summarize the knowledge regarding liver diseases, especially primary liver cancer (HCC) and the participation of chemokines in the development of this malignancy. Chemokines involved in the initiation of this type of tumor belong mainly to the CC and CXC chemokines. Their significant role in the course of hepatocellular carcinoma proves their usefulness in detecting and monitoring the course and treatment in patients with this disease. Full article

(This article belongs to the Special Issue Liver Cancer 2.0)

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6 pages, 859 KiB

Open AccessPerspective

IDH Inhibitors and Immunotherapy for Biliary Tract Cancer: A Marriage of Convenience?

by Giovanni Brandi and Alessandro Rizzo

Int. J. Mol. Sci. 2022, 23(18), 10869; https://doi.org/10.3390/ijms231810869 - 17 Sep 2022

Cited by 5 | Viewed by 1777

Abstract

Systemic treatments have traditionally reported limited efficacy for biliary tract cancer (BTC), and although targeted therapies and immune checkpoint inhibitors have been found to play an increasingly important role in treatment, several questions remain unanswered, including the identification of biomarkers of response. The [...] Read more.

Systemic treatments have traditionally reported limited efficacy for biliary tract cancer (BTC), and although targeted therapies and immune checkpoint inhibitors have been found to play an increasingly important role in treatment, several questions remain unanswered, including the identification of biomarkers of response. The tumor microenvironment (TME) has recently attracted the attention of the BTC medical community, and is currently being studied due to its potential role in modulating response and resistance to systemic therapies, including immunotherapy. In this perspective article, we discuss available evidence regarding the interplay between TME, IDH inhibitors, and immunotherapy, providing rationale for the design of future clinical trials. Full article

(This article belongs to the Special Issue Liver Cancer 2.0)

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