Molecular pathogenesis and systemic therapies for hepatocellular carcinoma

Llovet, Josep M.; Pinyol, Roser; Kelley, Robin K.; El-Khoueiry, Anthony B.; Reeves, Helen L.; Wang, Xin Wei; Gores, Gregory J.; Villanueva, Augusto

doi:10.1038/s43018-022-00357-2

Cited by 239 publications

(144 citation statements)

References 175 publications

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“…The etiology of liver cancer is very complex and often stems from multiple chronic diseases [ 1 , 3 ]. In European and American patients with liver cancer, glucose and lipid metabolism disorders, alcohol metabolism disorders, hepatitis C virus infection, and HBV infection account for 36.6, 23.5, 22.4, and 6.3% of cases, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Gene mutations account for 3.2% of cases [ 33 ]. Therefore, the prevention and treatment of these chronic diseases will effectively reduce the occurrence of liver cancer [ 1 , 3 , 4 ]. Moreover, the mechanisms with liver lesions induced by various etiologies are different, and a variety of signals are often pooled together to promote the development of the disease [ 3 , 5 ].…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the prevention and treatment of these chronic diseases will effectively reduce the occurrence of liver cancer [ 1 , 3 , 4 ]. Moreover, the mechanisms with liver lesions induced by various etiologies are different, and a variety of signals are often pooled together to promote the development of the disease [ 3 , 5 ]. Therefore, drugs targeting a single signaling pathway are usually inadequate to prevent and reverse the disease.…”

Section: Discussionmentioning

confidence: 99%

“…It also has a very high mortality rate and is the second leading cause of cancer deaths [ 1 , 2 ]. Hepatocellular carcinoma (HCC) and cholangiocarcinoma are the main subtypes of liver cancer and are often caused by infection with hepatitis B and C viruses (HBV and HCV), persistent aflatoxin exposure, alcohol consumption, smoking, metabolic abnormalities, and, to a lesser extent, genetic mutations [ 1 , 3 , 4 ]. Hepatocellular carcinoma (HCC) mainly develops from chronic diseases, including alcoholic and nonalcoholic steatohepatitis, diabetes mellitus, metabolic syndrome, and viral hepatitis [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…However, these treatments are not effective because most HCC patients are still in an advanced stage of disease [ 6 , 7 ]. Molecular targeted therapy and the recently emerging immunotherapy approaches have good prospects, but there are still few clinical applications, with only the drug sorafenib currently available [ 3 , 4 , 7 ]. As a result, the five-year survival rate of HCC patients has not risen in the past several decades [ 1 , 4 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

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miR-9 and miR-181a Target Gab2 to Inhibit the Proliferation and Migration of Hepatocellular Carcinoma HepG2 Cells

Huang

Liu

Zhou

et al. 2022

Genes

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The incidence of liver cancer ranks seventh globally, with nearly half of all cases occurring in East Asia, but currently, there are very few drugs to treat it. Our previous studies demonstrated that the signal integration protein Gab2 is a potential drug target for the prevention and therapy of liver cancer. Here, we screened for and identified two miRNAs that target Gab2 to suppress the proliferation and migration of hepatocellular carcinoma (HCC) cells. First, we predicted Gab2-targeting miRNAs through biological websites, and we selected nine miRNAs that were reported in the literature as being abnormally expressed in liver cancer and fatty liver tissue. Then, we measured the expression of these miRNAs in the hepatic epithelial cell line HL-7702 and the HCC cell line HepG2. The expression levels of miR-9, miR-181a, miR-181c, miR-34a, and miR-134 were high in HL-7702 cells but low in HepG2 cells, and their expression patterns were the opposite of Gab2 in these cells. Furthermore, we transfected miR-9, miR-34a, miR-181a, and miR-181c mimics into HepG2 cells and found that only miR-9 and miR-181a reduced the level of Gab2 proteins. miR-9 also reduced the Gab2 mRNA level, but miR-181a did not affect the Gab2 mRNA levels. Using a miRNA-Gab2 3′UTR binding reporter, we confirmed that miR-9 and miR-181a bind to the Gab2 3′UTR region. Finally, we introduced miR-9 and miR-181a mimics into HepG2 cells and found that cell proliferation and migration were significantly inhibited. In conclusion, we identified two novel miRNAs targeting Gab2 and provided potential drug targets for the prevention and treatment of liver cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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miR-9 and miR-181a Target Gab2 to Inhibit the Proliferation and Migration of Hepatocellular Carcinoma HepG2 Cells

Huang

Liu

Zhou

et al. 2022

Genes

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Critical Appraisal of Guideline Recommendations on Systemic Therapies for Advanced Hepatocellular Carcinoma

et al. 2024

Self Cite

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ImportanceThe combination of immune checkpoint inhibitors with antiangiogenic agents has revolutionized the treatment landscape of advanced hepatocellular carcinoma (HCC). However, due to rapid publication of new studies that attained their predefined primary end points, a lack of robust cross-trial comparison of first-line therapies, and diverging clinical guidelines, no clear-cut treatment flowchart and sequence of therapies are available. This critical analysis of the recommendations for the management of advanced HCC from the main scientific societies in the US and Europe adopted an integrated approach to provide information on the clinical benefit (overall survival and progression-free survival) and safety profile of these therapies using the European Society for Medical Oncology (ESMO)–Magnitude of Clinical Benefit Scale (MCBS) score and an ad hoc network meta-analysis.ObservationsThere is a major consensus among guidelines that atezolizumab plus bevacizumab has a primacy as the recommended first-line treatment of choice in advanced HCC. On progression after immunotherapy-containing regimens and for patients with contraindications for immunotherapies, most guidelines maintain the established treatment hierarchy, recommending lenvatinib or sorafenib as the preferred options, followed by either regorafenib, cabozantinib, or ramucirumab. Thus far, the first-line immune-based regimen of tremelimumab plus durvulumab has been integrated only in the American Association for the Study of Liver Diseases guidance document and the latest National Comprehensive Cancer Network guidelines and is recommended for patients with a high risk of gastrointestinal bleeding. Overall, in the first-line setting, both atezolizumab plus bevacizumab and sintilimab plus IBI305 (a bevacizumab biosimilar) received the highest ESMO-MCBS score of 5, indicating a substantial magnitude of clinical benefit. In a network meta-analysis, no significant differences in overall survival were found among the various combination regimens. However, the newly reported combination of camrelizumab plus rivoceranib was associated with a significantly higher risk of treatment-related adverse events compared with atezolizumab plus bevacizumab (relative risk, 1.59; 95% CI, 1.25-2.03; P &lt; .001).Conclusions and RelevanceThis narrative review found that atezolizumab plus bevacizumab is regarded as the primary standard of care for advanced HCC in the first-line setting. These findings from integrating the recommendations from scientific societies’ guidelines for managing advanced HCC along with new data from cross-trial comparisons may aid clinicians in decision-making and guide them through a rapidly evolving and complex treatment landscape.

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CSN6‐SPOP‐HMGCS1 Axis Promotes Hepatocellular Carcinoma Progression via YAP1 Activation

Li,

Zhang,

Lyu

et al. 2024

Advanced Science

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Cholesterol metabolism has important roles in maintaining membrane integrity and countering the development of diseases such as obesity and cancers. Cancer cells sustain cholesterol biogenesis for their proliferation and microenvironment reprograming even when sterols are abundant. However, efficacy of targeting cholesterol metabolism for cancer treatment is always compromised. Here it is shown that CSN6 is elevated in HCC and is a positive regulator of hydroxymethylglutaryl‐CoA synthase 1 (HMGCS1) of mevalonate (MVA) pathway to promote tumorigenesis. Mechanistically, CSN6 antagonizes speckle‐type POZ protein (SPOP) ubiquitin ligase to stabilize HMGCS1, which in turn activates YAP1 to promote tumor growth. In orthotopic liver cancer models, targeting CSN6 and HMGCS1 hinders tumor growth in both normal and high fat diet. Significantly, HMGCS1 depletion improves YAP inhibitor efficacy in patient derived xenograft models. The results identify a CSN6‐HMGCS1‐YAP1 axis mediating tumor outgrowth in HCC and propose a therapeutic strategy of targeting non‐alcoholic fatty liver diseases‐ associated HCC.

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Molecular pathogenesis and systemic therapies for hepatocellular carcinoma

Cited by 239 publications

References 175 publications

miR-9 and miR-181a Target Gab2 to Inhibit the Proliferation and Migration of Hepatocellular Carcinoma HepG2 Cells

miR-9 and miR-181a Target Gab2 to Inhibit the Proliferation and Migration of Hepatocellular Carcinoma HepG2 Cells

Critical Appraisal of Guideline Recommendations on Systemic Therapies for Advanced Hepatocellular Carcinoma

CSN6‐SPOP‐HMGCS1 Axis Promotes Hepatocellular Carcinoma Progression via YAP1 Activation

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