Novel feedback inhibition of surface antigen synthesis by mammalian target of rapamycin (mTOR) signal and its implication for hepatitis B virus tumorigenesis and therapy

Teng, Chiao-Fang; Wu, Han Chieh; Tsai, Hung Wen; Shiah, Her Shyong; Huang, Wenya; Su, Ih Jen

doi:10.1002/hep.24529

Cited by 58 publications

(63 citation statements)

References 36 publications

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“…Using our 3D system, we showed that retroV-TCR T cells maintained their antitumor function, despite exposure to immunosuppressive rapamycin. The exact mechanism remains to be elucidated, but previous reports showing increased HBsAg expression in hepatoma cells treated with mTOR inhibitors (27) and the improved survival in low-risk transplanted patients immunosuppressed with rapamycin (28) provided an immunological rationale for our observation.…”

Section: Discussionmentioning

confidence: 92%

A 3D microfluidic model for preclinical evaluation of TCR-engineered T cells against solid tumors

et al. 2017

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Section: Discussionmentioning

confidence: 92%

A 3D microfluidic model for preclinical evaluation of TCR-engineered T cells against solid tumors

et al. 2017

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“…Total RNA was extracted and converted to cDNA as described previously (23). Real-time PCR was performed with the LightCycler system and the mouse Universal ProbeLibrary system (Roche Applied Science, Indianapolis, IN).…”

Section: Methodsmentioning

confidence: 99%

“…Western blot analysis was performed as previously described (23). The primary antibodies used in this study were anti-pmTOR (Ser2448), anti-SREBF1, anti-FADS2 (Abcam, Cambridge, United Kingdom), anti-ACLY, anti-pACLY (Ser455) (Cell Signaling Technology, Danvers, MA), anti-acetyl-histone H3 (Millipore, Bedford, MA), anti-HA tag (Zymed Laboratories, South San Francisco, CA), and anti-ACTB (actin, beta) (Chemicon, Temecula, CA).…”

Section: Methodsmentioning

confidence: 99%

Activation of ATP Citrate Lyase by mTOR Signal Induces Disturbed Lipid Metabolism in Hepatitis B Virus Pre-S2 Mutant Tumorigenesis

Teng

Hsieh

et al. 2015

J Virol

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The development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) has been found to be associated with disturbed lipid metabolism. To elucidate the role of lipid metabolism in HBV tumorigenesis, we investigated the dynamic pattern of lipid metabolism in HBV pre-S2 mutant-induced tumorigenesis. Lipid and gene expression profiles were analyzed in an in vitro culture system and in transgenic mouse livers harboring HBV pre-S2 mutant. The pre-S2 mutant transgenic livers showed a biphasic pattern of lipid accumulation, starting from mild fatty change in early (1 month) transgenic livers, which subsided and then, remarkably, increased in HCC tissues. This biphasic pattern was synchronized with ATP citrate lyase (ACLY) activation. Further analyses revealed that the pre-S2 mutant initiated an endoplasmic reticulum (ER) stress-dependent mammalian target of rapamycin (mTOR) signalling cascade. The pre-S2 mutant-induced mTOR signal activated the sterol regulatory element binding transcription factor 1 (SREBF1) to upregulate ACLY, which then activated the fatty acid desaturase 2 (FADS2), mediated through ACLY-dependent histone acetylation. Such an ER stress-dependent mTOR signal cascade also is important for the proliferation of hepatocytes in vitro and is further validated in HBV-related HCC tissues. IMPORTANCEAberrations of lipid metabolism frequently occur in chronic HBV infection. Our results provide a potential mechanism of disturbed lipid metabolism in HBV pre-S2 mutant-induced tumorigenesis, which should be valuable for the design of HCC chemoprevention in high-risk HBV carriers.

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“…[258] Protein kinase C (PI3K) is also activated by HBx, [259, 260] which correlates with recent results suggesting HBV and HBx activate the PI3K/Akt pathway, reducing HBV replication. [86, 233] In addition, studies have shown that mutant L-HBsAg can activate mTOR signaling, [261–263] ultimately causing increased lipogenesis. [262] …”

Section: Hbv and Hccmentioning

confidence: 99%

Hepatitis B virus molecular biology and pathogenesis

Lamontagne¹,

Bagga²,

Bouchard³

2016

146

109

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As obligate intracellular parasites, viruses need a host cell to provide a milieu favorable to viral replication. Consequently, viruses often adopt mechanisms to subvert host cellular signaling processes. While beneficial for the viral replication cycle, virus-induced deregulation of host cellular signaling processes can be detrimental to host cell physiology and can lead to virus-associated pathogenesis, including, for oncogenic viruses, cell transformation and cancer progression. Included among these oncogenic viruses is the hepatitis B virus (HBV). Despite the availability of an HBV vaccine, 350–500 million people worldwide are chronically infected with HBV, and a significant number of these chronically infected individuals will develop hepatocellular carcinoma (HCC). Epidemiological studies indicate that chronic infection with HBV is the leading risk factor for the development of HCC. Globally, HCC is the second highest cause of cancer-associated deaths, underscoring the need for understanding mechanisms that regulate HBV replication and the development of HBV-associated HCC. HBV is the prototype member of the Hepadnaviridae family; members of this family of viruses have a narrow host range and predominately infect hepatocytes in their respective hosts. The extremely small and compact hepadnaviral genome, the unique arrangement of open reading frames, and a replication strategy utilizing reverse transcription of an RNA intermediate to generate the DNA genome are distinguishing features of the Hepadnaviridae. In this review, we provide a comprehensive description of HBV biology, summarize the model systems used for studying HBV infections, and highlight potential mechanisms that link a chronic HBV-infection to the development of HCC. For example, the HBV X protein (HBx), a key regulatory HBV protein that is important for HBV replication, is thought to play a cofactor role in the development of HBV-induced HCC, and we highlight the functions of HBx that may contribute to the development of HBV-associated HCC.

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Novel feedback inhibition of surface antigen synthesis by mammalian target of rapamycin (mTOR) signal and its implication for hepatitis B virus tumorigenesis and therapy

Cited by 58 publications

References 36 publications

A 3D microfluidic model for preclinical evaluation of TCR-engineered T cells against solid tumors

A 3D microfluidic model for preclinical evaluation of TCR-engineered T cells against solid tumors

Activation of ATP Citrate Lyase by mTOR Signal Induces Disturbed Lipid Metabolism in Hepatitis B Virus Pre-S2 Mutant Tumorigenesis

Hepatitis B virus molecular biology and pathogenesis

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