The hepatitis B virus X protein promotes pancreatic cancer through modulation of the PI3K/AKT signaling pathway

PURPOSE. Our study aimed to evaluate the side effects of selective serotonin reuptake inhibitors (SSRIs) on the ocular surface. METHODS. Twenty patients with depression and dry eye disease (DED) were randomly picked to receive SSRI treatment, whereas another 20 patients received placebo treatment. The serotonin, inflammatory cytokine, and proapoptotic protein levels were determined by using protein chip, qRT-PCR, and ELISA analyses. A rat depression model was established, and SSRIs were applied for 3 or 6 weeks. Tear production and corneal epithelial barrier function were evaluated. The serotonin and inflammatory cytokine levels were analyzed by qRT-PCR, immunohistochemical staining, and ELISA. Human corneal epithelial cells were subjected to serotonin, a HTR antagonist, and/or an NF-jB signaling inhibitor. The inflammatory cytokine and proapoptotic protein levels were determined by qRT-PCR, Western blot analysis, and ELISA. The cell apoptosis rate was assessed by using flow cytometry. RESULTS. The SSRI group had higher tear serotonin levels and more serious inflammation and cell apoptosis on the ocular surface. In the rat depression model, depression decreased tear secretion and increased IL-1b and TNF-a production, whereas the serotonin, TLR2, and TLR4 levels were not increased. SSRI aggravated DED, disrupted the corneal epithelial barrier, and promoted an inflammatory response on the ocular surface by increasing the tear serotonin levels. In addition, serotonin induced an inflammatory response and cell apoptosis in corneal epithelial cells by activating NF-jB signaling. CONCLUSIONS. SSRIs aggravate depression-associated DED via activating the NF-jB pathway. The antagonist of HTRs or the inhibitor of NF-jB signaling presents a potential therapeutic strategy for depression-associated DED. (Trial registration number, ChiCTR1800015592).

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“…Supernatants were collected by centrifugation at 2000g for 10 minutes and were tested by the protein array company. 19…”

Section: Protein Chipmentioning

confidence: 99%

Selective Serotonin Reuptake Inhibitors Aggravate Depression-Associated Dry Eye Via Activating the NF-κB Pathway

Zhang

Yin

Yue

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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“…HBV infection has also been associated with cancers at other extrahepatic sites (e.g., colorectum, kidney and ovaries) . Besides the hepatocytes, HBV DNA sequences have been found in extrahepatic tissues such as pancreas, biliary tract and kidney, as well as lymphatic tissue and peripheral mononuclear cells, thus making associations with cancer biologically plausible …”

Section: Introductionmentioning

confidence: 99%

“…10 Besides the hepatocytes, HBV DNA sequences have been found in extrahepatic tissues such as pancreas, biliary tract and kidney, as well as lymphatic tissue and peripheral mononuclear cells, thus making associations with cancer biologically plausible. [11][12][13][14][15][16] Population-based studies in the US that analyzed the association between HBV infection and cancer have mostly focused on hepatobiliary cancers. [17][18][19] HBV infection is currently not considered a major public health problem in the general US population due to widespread implementation of HBV vaccination at birth since 1992.…”

Section: Introductionmentioning

confidence: 99%

Hepatitis B virus infection and the risk of cancer in the elderly US population

Mahale

Engels

Koshiol

2018

Intl Journal of Cancer

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Hepatitis B virus (HBV) infection causes hepatocellular carcinoma (HCC). Associations with other cancers are not established. We systematically assessed associations between HBV infection and cancers in the US elderly population. We conducted a case-control study using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database in US adults aged ≥66 years. Cases (N = 1,825,316) were people with first cancers diagnosed in SEER registries (1993-2013). Controls (N = 200,000) were randomly selected, cancer-free individuals who were frequency-matched to cases on age, sex, race and calendar year. Associations with HBV infection (ascertained by Medicare claims) were assessed by logistic regression. HBV prevalence was higher in cases than controls (0.6% vs. 0.5%). HBV was positively associated with cancers of the stomach (adjusted odds ratio [aOR] = 1.19; 95% confidence intervals [CI] = 1.03-1.37), anus (1.66; 1.17-2.33), liver (10.6; 9.66-11.6), intrahepatic bile ducts (1.67; 1.18-2.37), nasopharynx (2.08; 1.33-3.25), as well as myelodysplastic syndrome (1.26; 1.07-1.49) and diffuse large B-cell lymphoma (DLBCL) (1.24; 1.06-1.46). Inverse associations were observed with female breast (aOR = 0.86; 95%CI = 0.76-0.98) and prostate (0.81; 0.73-0.91) cancers and chronic lymphocytic leukemia (0.77; 0.62-0.96). Associations were maintained in sensitivity analyses conducted in people without claims for cirrhosis or hepatitis C or human immunodeficiency virus infections. HBV infection is associated with increased risk of cancers other than HCC, such as bile duct cancers and DLBCL. The biological mechanisms by which HBV may lead to these cancers need to be explored.

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“…Besides the class I PI3K/AKT/mTOR and class III PI3K/beclin-1 signaling pathways, MAPKs (ERK, p38, and JNK) may also play an important role in autophagy induction (21), while HBx, as a multifunctional protein, is well known for its role in the regulation of diverse signaling pathways (41,42). We therefore further examined the contribution of MAPKs to HBx-induced autophagosome formation.…”

mentioning

confidence: 99%

Reactive Oxygen Species-Mediated c-Jun NH ₂ -Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction

Zhong

Shu

Dai

et al. 2017

J Virol

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Autophagy is closely associated with the regulation of hepatitis B virus (HBV) replication. HBV X protein (HBx), a multifunctional regulator in HBV-associated biological processes, has been demonstrated to be crucial for autophagy induction by HBV. However, the molecular mechanisms of autophagy induction by HBx, especially the signaling pathways involved, remain elusive. In the present investigation, we demonstrated that HBx induced autophagosome formation independently of the class I phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling pathway. In contrast, the class III PI3K(VPS34)/beclin-1 pathway was revealed to be critical for HBx-induced autophagosome formation. Further study showed that HBx did not affect the level of VPS34 and beclin-1 expression but inhibited beclin-1/Bcl-2 association, and c-Jun NH2-terminal kinase (JNK) signaling was found to be important for this process. Moreover, it was found that HBx treatment led to the generation of reactive oxygen species (ROS), and inhibition of ROS activity abrogated both JNK activation and autophagosome formation. Of importance, ROS-JNK signaling was also revealed to play an important role in HBV-induced autophagosome formation and subsequent HBV replication. These data may provide deeper insight into the mechanisms of autophagy induction by HBx and help in the design of new therapeutic strategies against HBV infection.IMPORTANCE HBx plays a key role in diverse HBV-associated biological processes, including autophagy induction. However, the molecular mechanisms of autophagy induction by HBx, especially the signaling pathways involved, remain elusive. In the present investigation, we found that HBx induced autophagy independently of the class I PI3K/AKT/mTOR signaling pathway, while the class III PI3K(VPS34)/beclin-1 pathway was revealed to be crucial for this process. Further data showed that ROS-JNK activation by HBx resulted in the release of beclin-1 from its association with Bcl-2 to form a complex with VPS34, thus enhancing autophagosome formation. Of importance, ROS-JNK signaling was also demonstrated to be critical for HBV replication via regulation of autophagy induction. These data help to elucidate the molecular mechanisms of autophagy induction by HBx/HBV and might be useful for designing novel therapeutic approaches to HBV infection.KEYWORDS HBV X protein, autophagy, signaling pathway, viral replication H epatitis B virus (HBV) is an important human pathogen that can cause a wide spectrum of liver diseases, including hepatitis, liver cirrhosis, and hepatocellular carcinoma (1, 2). The HBV genome is about 3.2 kb in length, carrying four genes named

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The hepatitis B virus X protein promotes pancreatic cancer through modulation of the PI3K/AKT signaling pathway

Cited by 40 publications

References 36 publications

Selective Serotonin Reuptake Inhibitors Aggravate Depression-Associated Dry Eye Via Activating the NF-κB Pathway

Selective Serotonin Reuptake Inhibitors Aggravate Depression-Associated Dry Eye Via Activating the NF-κB Pathway

Hepatitis B virus infection and the risk of cancer in the elderly US population

Reactive Oxygen Species-Mediated c-Jun NH ₂ -Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction

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The hepatitis B virus X protein promotes pancreatic cancer through modulation of the PI3K/AKT signaling pathway

Cited by 40 publications

References 36 publications

Selective Serotonin Reuptake Inhibitors Aggravate Depression-Associated Dry Eye Via Activating the NF-κB Pathway

Selective Serotonin Reuptake Inhibitors Aggravate Depression-Associated Dry Eye Via Activating the NF-κB Pathway

Hepatitis B virus infection and the risk of cancer in the elderly US population

Reactive Oxygen Species-Mediated c-Jun NH 2 -Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction

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Reactive Oxygen Species-Mediated c-Jun NH ₂ -Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction