Mutations in TP53, CTNNB1 and PIK3CA genes in hepatocellular carcinoma associated with hepatitis B and hepatitis C virus infections

Tornesello, Maria Lina; Buonaguro, Luigi; Tatangelo, Fabiana; Botti, Gerardo; Izzo, Francesco; Buonaguro, Franco M.

doi:10.1016/j.ygeno.2013.04.001

Cited by 150 publications

(122 citation statements)

References 106 publications

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“…Somatic and inherited mutations in APC leading to prematurely truncated protein are most frequently found in colorectal cancers (49). Mutations in b-catenin altering or deleting the GSK3 phosphorylation sites (Ser33, Ser37, and Thr41) are reported in various cancers, including pancreatic, gastric, liver, and endometrial cancers (64). These mutations prevent b-catenin degradation, leading to enhanced LEF/TCF-mediated transcription.…”

Section: Mutations That May Sensitize Cancer Cells To Secreted Wnt LImentioning

confidence: 99%

Targeting Wnts at the Source—New Mechanisms, New Biomarkers, New Drugs

Madan

Virshup

2015

Molecular Cancer Therapeutics

100

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Wnt signaling is dysregulated in many cancers and is therefore an attractive therapeutic target. The focus of drug development has recently shifted away from downstream inhibitors of b-catenin. Active inhibitors of Wnt secretion and Wnt/receptor interactions have been developed that are now entering clinical trials. Such agents include inhibitors of Wnt secretion, as well as recombinant proteins that minimize Wnt-Frizzled interactions. These new therapies arrive together with the recent insight that cancer-specific upregulation of Wnt receptors at the cell surface regulates cellular sensitivity to Wnts. Loss-of-function mutations in RNF43 or ZNRF3 and gain-of-function chromosome translocations involving RSPO2 and RSPO3 are surprisingly common and markedly increase Wnt/b-catenin signaling in response to secreted Wnts. These mutations may be predictive biomarkers to select patients responsive to newly developed upstream Wnt inhibitors.

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Section: Mutations That May Sensitize Cancer Cells To Secreted Wnt LImentioning

confidence: 99%

Targeting Wnts at the Source—New Mechanisms, New Biomarkers, New Drugs

Madan

Virshup

2015

Molecular Cancer Therapeutics

100

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“…Four-parameter logistic model was applied to calculate IC 50 . The two-tailed Student t test was applied for paired data analysis.…”

Section: Discussionmentioning

confidence: 99%

“…Over 50% of human aflatoxininduced HCC harbor G249T mutation (47), while non-aflatoxin-induced, HBV-related and HCV-induced HCC have low mutation rate (48,49). More importantly, deletion of p53 is rare in human HCC (50). Therefore, Rubone is a suitable agent to treat HCC that retains p53 in cancer cells.…”

Section: Mir34a Modulator Inhibited Proliferation and Induced Apoptosmentioning

confidence: 99%

A Small-Molecule Modulator of the Tumor-Suppressor miR34a Inhibits the Growth of Hepatocellular Carcinoma

Xiao

Chan

et al. 2014

Cancer Research

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Small molecules that restore the expression of growth-inhibitory microRNAs (miRNA) downregulated in tumors may have potential as anticancer agents. miR34a functions as a tumor suppressor and is downregulated or silenced commonly in a variety of human cancers, including hepatocellular carcinoma (HCC). In this study, we used an HCC cell-based miR34a luciferase reporter system to screen for miR34a modulators that could exert anticancer activity. One compound identified as a lead candidate, termed Rubone, was identified through its ability to specifically upregulate miR34a in HCC cells. Rubone activated miR34a expression in HCC cells with wildtype or mutated p53 but not in cells with p53 deletions. Notably, Rubone lacked growth-inhibitory effects on nontumorigenic human hepatocytes. In a mouse xenograft model of HCC, Rubone dramatically inhibited tumor growth, exhibiting stronger anti-HCC activity than sorafenib both in vitro and in vivo. Mechanistic investigations showed that Rubone decreased expression of cyclin D1, Bcl-2, and other miR34a target genes and that it enhanced the occupancy of p53 on the miR34a promoter. Taken together, our results offer a preclinical proof of concept for Rubone as a lead candidate for further investigation as a new class of HCC therapeutic based on restoration of miR34a tumor-suppressor function. Cancer Res; 74(21); 6236-47. Ó2014 AACR.

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“…In countries where HCV infection is endemic (Japan or some areas of Southern Italy), a high prevalence of HCV infection has been reported among people with HCC [14,15]. Several studies found a three-fold increase in HCV-related HCC, whereas the rate of HCC associated with HBV or alcohol-induced liver disease and idiopathic cirrhosis remained stable [2,16].…”

Section: Introductionmentioning

confidence: 99%

Hepatitis C Virus (HCV) genotypes distribution among hepatocellular carcinoma patients in Southern Italy: a three year retrospective study

Petruzziello

Marigliano

Loquercio

et al. 2017

Infect Agents Cancer

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Background: Hepatocellular carcinoma (HCC) is one of the major cause for cancer in the world. Aim of this casecontrol study was to investigate the distribution pattern of HCV genotypes among HCC patients and suggest whether infection with specific subtypes may be associated with an increased risk of progression to cancer. Methods: 152 HCC anti-HCV positive patients, fulfilling the criteria from the Barcelona 2000 EASL conference, and 568 patients HCV chronically infected but without HCC as control group were included in the study. Serum of each patient was evaluated for viral load estimation and genotyping. Results: Males with HCC significantly showed to have quite 2 times higher risk of exposure to HCV infection (OR = 1.72; 95% CI = 1.15-2.58). Moreover, HCC was significantly associated with older age. In fact, > 50 years older patients showed to have a higher risk of developing HCC (OR = 17.4; 95% CI = 4.24 to 71.36) compared to younger patients. HCV RNA rate was significantly higher (83.7%) among HCC patients than in the control group (61.4%, p < 0.001) and the most prevalent genotype was 1b (68.0% in HCC vs 54.4% in the control group, p < 0.005). HCC patients significantly have a risk of exposure to HCV 1b infection almost 2 times greater than the control group (OR = 1.8; 95% CI = 1.11-2.82). The multivariate-adjusted OR (95% CI) of developing HCC for HCV 1b comparing to non-1b was 1.65 (1.16-2.33). Conclusions: Our study detected a significantly higher rate of HCV RNA positivity and a higher rate of HCV 1b infection in HCC patients, suggesting the strict association between subtype 1b infection and HCC. A prospective study with larger number of samples would be needed to confirm our results.

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Mutations in TP53, CTNNB1 and PIK3CA genes in hepatocellular carcinoma associated with hepatitis B and hepatitis C virus infections

Cited by 150 publications

References 106 publications

Targeting Wnts at the Source—New Mechanisms, New Biomarkers, New Drugs

Targeting Wnts at the Source—New Mechanisms, New Biomarkers, New Drugs

A Small-Molecule Modulator of the Tumor-Suppressor miR34a Inhibits the Growth of Hepatocellular Carcinoma

Hepatitis C Virus (HCV) genotypes distribution among hepatocellular carcinoma patients in Southern Italy: a three year retrospective study

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