Hepatitis B Virus X Upregulates HuR Protein Level to Stabilize HER2 Expression in Hepatocellular Carcinoma Cells

Hepatitis B virus- (HBV-) associated hepatocellular carcinoma (HCC) is the most common type of liver cancer. However, the underlying mechanism of HCC tumorigenesis is very complicated and HBV-encoded X protein (HBx) has been reported to play the most important role in this process. Activation of downstream signal pathways of epidermal growth factor receptor (EGFR) family is known to mediate HBx-dependent HCC tumor progression. Interestingly, HER2 (also known as ErbB2/Neu/EGFR2) is frequently overexpressed in HBx-expressing HCC patients and is associated with their poor prognosis. However, it remains unclear whether and how HBx regulates HER2 expression. In this study, our data showed that HBx expression increased HER2 protein level via enhancing its mRNA stability. The induction of RNA-binding protein HuR expression by HBx mediated the HER2 mRNA stabilization. Finally, the upregulated HER2 expression promoted the migration ability of HBx-expressing HCC cells. These findings deciphered the molecular mechanism of HBx-mediated HER2 upregulation in HBV-associated HCC.

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Pre-S2 Mutant-Induced Mammalian Target of Rapamycin Signal Pathways as Potential Therapeutic Targets for Hepatitis B Virus-Associated Hepatocellular Carcinoma

Cell Transplantation ◽

10.3727/096368916x694382 ◽

2017 ◽

Vol 26 (3) ◽

pp. 429-438 ◽

Cited By ~ 11

Author(s):

Chiao-Fang Teng ◽

Han-Chieh Wu ◽

Woei-Cherng Shyu ◽

Long-Bin Jeng ◽

Ih-Jen Su

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Er Stress ◽

Mammalian Target Of Rapamycin ◽

Hbv Infection ◽

Target Of Rapamycin ◽

Signal Pathways ◽

Type Ii ◽

B Virus

Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). Pre-S2 mutant represents an HBV oncoprotein that is accumulated in the endoplasmic reticulum (ER) and manifests as type II ground glass hepatocytes (GGHs). Pre-S2 mutant can induce ER stress and initiate multiple ER stress-dependent or -independent cellular signal pathways, leading to growth advantage of type II GGH. Importantly, the mammalian target of rapamycin (mTOR) signal pathways are consistently activated throughout the liver tumorigenesis in pre-S2 mutant transgenic mice and in human HCC tissues, leading to hepatocyte proliferation, metabolic disorders, and HCC tumorigenesis. In this review, we summarize the pre-S2 mutant-induced mTOR signal pathways and its implications in HBV-related HCC tumorigenesis. Clinically, the presence of pre-S2 mutant exhibits a high resistance to antiviral treatment and carries a high risk of HCC development in patients with chronic HBV infection. Targeting at pre-S2 mutant-induced mTOR signal pathways may thus provide potential strategies for the prevention or therapy of HBV-associated HCC.

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Serum Wisteria floribunda agglutinin-positive human Mac-2 binding protein level predicts recurrence of hepatitis B virus-related hepatocellular carcinoma after curative resection

Clinical and Molecular Hepatology ◽

10.3350/cmh.2018.0073 ◽

2020 ◽

Vol 26 (1) ◽

pp. 33-44 ◽

Cited By ~ 3

Author(s):

Hye Soo Kim ◽

Seung Up Kim ◽

Beom Kyung Kim ◽

Jun Yong Park ◽

Do Young Kim ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Protein Level ◽

Curative Resection ◽

Binding Protein ◽

B Virus ◽

Wisteria Floribunda

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Hepatitis B Virus Pre-S Mutants as Biomarkers and Targets for the Development and Recurrence of Hepatocellular Carcinoma

Viruses ◽

10.3390/v12090945 ◽

2020 ◽

Vol 12 (9) ◽

pp. 945 ◽

Cited By ~ 1

Author(s):

Chiao-Fang Teng ◽

Han-Chieh Wu ◽

Ih-Jen Su ◽

Long-Bin Jeng

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Hbv Infection ◽

Signal Pathways ◽

Recurrence Rates ◽

Chronic Hepatitis B Virus ◽

B Virus

Chronic hepatitis B virus (HBV) infection is a major risk factor for the development of hepatocellular carcinoma (HCC), the leading cause of cancer-related death worldwide. Despite progress in the prevention and therapy of HCC, high incidence and recurrence rates of HCC remain big threats, resulting in poor patient survival. Effective biomarkers and targets of HCC are therefore urgently needed for better management and to improve patient outcomes. Pre-S mutants have been well demonstrated as HBV oncoproteins that play important roles in HCC development through activation of multiple oncogenic signal pathways in hepatocytes, in vitro and in vivo. The presence of pre-S mutants in patients with chronic HBV infection and HBV-related HCC has been associated with a significantly higher risk of HCC development and recurrence after curative surgical resection, respectively. In this review, we summarize the roles of pre-S mutants as biomarkers for predicting HBV-related HCC development and recurrence, and highlight the pre-S mutants-activated oncogenic signal pathways as potential targets for preventing HBV-related HCC development.

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SerumWisteria floribundaagglutinin-positive Mac-2 binding protein level as a diagnostic marker of hepatitis B virus-related hepatocellular carcinoma

Hepatology Research ◽

10.1111/hepr.13187 ◽

2018 ◽

Vol 48 (11) ◽

pp. 872-881 ◽

Cited By ~ 3

Author(s):

Natthaya Chuaypen ◽

Salyavit Chittmittraprap ◽

Nutcha Pinjaroen ◽

Boonchoo Sirichindakul ◽

Yong Poovorawan ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Protein Level ◽

Diagnostic Marker ◽

Binding Protein ◽

B Virus

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

10.21203/rs.3.rs-860409/v1 ◽

2021 ◽

Author(s):

Hiroaki Kanzaki ◽

Tetsuhiro Chiba ◽

Tatsuya Kaneko ◽

Junjie Ao ◽

Na Qiang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Cell Growth ◽

Hepatitis B ◽

Rna Binding ◽

Primary Hepatocellular Carcinoma ◽

Control Group ◽

Loss Of Function ◽

Hbv Replication ◽

B Virus

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 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 have also been 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. Cell growth in tetracycline-treated replication-stopping HepAD38 cells was more significantly impaired in ELAVL1 knockdown than those in the control group, indicating that ELAVL1 is involved in proliferation not only by the suppression of HBV replication but also by other factors. Immunohistochemical analyses of 77 paired HCC surgical specimens have demonstrated that diffuse ELAVL1 expression was detected more frequently in HCC tissues (61.0%) than in nontumor 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.

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Role of environmental factors in the etiology of hepatocellular carcinoma

Orvosi Hetilap ◽

10.1556/oh.2010.28913 ◽

2010 ◽

Vol 151 (28) ◽

pp. 1132-1136 ◽

Cited By ~ 7

Author(s):

István Tornai

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Environmental Factors ◽

Hepatitis B ◽

Hepatitis A ◽

Virus Hepatitis ◽

B Virus

A krónikus vírushepatitisek jelentik ma a legismertebb okokat a hepatocellularis carcinoma (HCC) kialakulásában. A krónikus B- és C-vírus-hepatitis a májrákok körülbelül 40-50%-át okozza. A nyugati típusú társadalmakban a HCC előfordulása folyamatosan növekvő tendenciát mutat. Az alkohol számít a környezeti tényezők közül a legfontosabbnak, bár az alkoholfogyasztás a legtöbb országban csökken. Ez aláhúzza az egyéb környezeti tényezők fontosságát is. Az elfogyasztott alkoholmennyiséggel egyenes arányban növekszik a cirrhosis és a következményes HCC gyakorisága nőkben és férfiakban egyaránt. A kémiai anyagok közül a legismertebb a Kínában és Afrikában elterjedt aflatoxin, amely a gabonaféléket szennyező mycotoxin. Hasonló területeken endémiás, mint a hepatitis B-vírus, együtt szinergista hatást fejtenek ki. A dohányzás is egyértelműen bizonyított hepatocarcinogen hatással rendelkezik. Ez is jelentősen fokozódik, ha alkoholfogyasztással vagy vírushepatitisszel társul. Társadalmilag talán a legfontosabb az elhízás, a következményes nem alkoholos zsírmáj, illetve steatohepatitis és a 2-es típusú cukorbetegség, amelyek prevalenciája egyre fokozódik. Feltehetően ezek állnak a növekvő HCC-gyakoriság hátterében. Az inzulinrezisztencia és az oxidatív stressz képezik a legfontosabb patogenetikai lépéseket a májsejtkárosodásban. További fontos rizikótényező az orális fogamzásgátlók elterjedt használata. Egyes foglalkozások esetén a tartós szervesoldószer-expozíció is növeli a HCC rizikóját. Védelmet jelenthetnek az antioxidánsok, a szelén, a gyógyszerek közül a statinok és a feketekávé-fogyasztás.

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