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Cited by 5

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HBV upregulates AP‑1 complex subunit mu‑1 expression via the JNK pathway to promote proliferation of liver cancer cells

Kou, Yanbo, Yan, Xiaoqing, Liu, Qingya, Wei, Xiao, Zhang, Bo, Li, Xiangyang, Pan, Wei, Kong, Fanyun, Wang, Yugang, Zheng, Kuiyang, Tang, Renxian·2019·Oncology Letters
DOI 10.3892/ol.2019.10291PMC PMC6540315
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Abstract

Although hepatitis B virus (HBV) infection is responsible for liver cancer, the exact mechanism of its action remains unclear. μ1 adaptin is an intrinsic part of the clathrin adaptor AP‑1 complex. In addition to its canonical biological function that involves cargo sorting and vesicular transport, recent studies have demonstrated that μ1 adaptin participates in cell growth and proliferation. The aim of the present study was to investigate the effects of the clathrin adaptor AP‑1 complex subunit mu‑1 (AP1M1) on liver cancer cell proliferation. The present study reports for the first time that AP1M1 is upregulated in the HBV‑transfected HepG2.215 liver cancer cells. Silencing of AP1M1 in HepG2.215 cells suppressed their proliferation, while the overexpression of AP1M1 in HepG2 cells promoted cell proliferation. The data suggested that AP1M1 is one of the crucial factors involved in the progression of liver cancer caused by HBV infection. In addition, it was demonstrated that HBV facilitated AP1M1 expression in a JNK‑dependent manner. The increased expression levels of AP1M1 enhanced phosphorylation of protein kinase B and accelerated cell proliferation. Unraveling the effects of AP1M1 on liver cancer cell proliferation and the mechanism of AP1M1 transcriptional regulation may provide new therapeutic targets for HBV‑positive liver cancer.

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Crossref · 10.3892/ol.2019.10291

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Figures

Figure 1. AP1M1 is upregulated in HBV-positive liver cancer cells. (A) Relative quantity of AP1M1 mRNA levels from L02, Huh7, HepG2 and HepG2.215 cells. (B) AP1M1 protein expression analysis was detected by western blotting in L02, Huh7, HepG2 and HepG2.215 cells. (C) The quantification of the proteins was performed by densitometry. (D) The relative transcription of AP1M1 in liver tissues of acute liver failure patients with or without HBV infection. *P<0.05, **P<0.01 and ***P<0.001. HBV, hepatitis B virus.
Figure 1. AP1M1 is upregulated in HBV-positive liver cancer cells. (A) Relative quantity of AP1M1 mRNA levels from L02, Huh7, HepG2 and HepG2.215 cells. (B) AP1M1 protein expression analysis was detected by western blotting in L02, Huh7, HepG2 and HepG2.215 cells. (C) The quantification of the proteins was performed by densitometry. (D) The relative transcription of AP1M1 in liver tissues of acute liver failure patients with or without HBV infection. *P<0.05, **P<0.01 and ***P<0.001. HBV, hepatitis B virus.CC BY-NC-ND · PubMed Central
Figure 2. Upregulation of AP1M1 mediated by HBV promotes liver cancer cell proliferation. (A) Western blot analysis of AP1M1 from HepG2.215 cells with or without siRNA and (B) quantification of the proteins was performed by densitometry. (C) AP1M1 protein expression by western blot analysis in HepG2 cells overexpressing AP1M1 and control cells. (D) The quantification of the proteins was performed by densitometry. (E) Cell Counting Kit-8 and (F) colony formation assay analysis of cell proliferation among HepG2-NC, HepG2-OEAP1M1, HepG2.215 and HepG2.215-siAP1M1 cells. *P<0.05, **P<0.01 and ***P<0.001. HBV, hepatitis B virus; si, small interfering; NC, negative control.
Figure 2. Upregulation of AP1M1 mediated by HBV promotes liver cancer cell proliferation. (A) Western blot analysis of AP1M1 from HepG2.215 cells with or without siRNA and (B) quantification of the proteins was performed by densitometry. (C) AP1M1 protein expression by western blot analysis in HepG2 cells overexpressing AP1M1 and control cells. (D) The quantification of the proteins was performed by densitometry. (E) Cell Counting Kit-8 and (F) colony formation assay analysis of cell proliferation among HepG2-NC, HepG2-OEAP1M1, HepG2.215 and HepG2.215-siAP1M1 cells. *P<0.05, **P<0.01 and ***P<0.001. HBV, hepatitis B virus; si, small interfering; NC, negative control.CC BY-NC-ND · PubMed Central
Figure 3. HBX facilitates AP1M1 expression in liver cancer cells. (A) HBX mRNA was detected by reverse transcription-PCR. (B) AP1M1 protein expression analysis by western blotting of HepG2-NC, HepG2-HBX, HepG2.215 and HepG2.215ΔHBX cells. (C) Quantitative PCR analysis of AP1M1 transcription in HepG2-NC, HepG2-HBX, HepG2.215 and HepG2.215ΔHBX cells. (D) Dual luciferase assay analysis of AP1M1 promoter activity in HepG2-NC, HepG2-HBX, HepG2.215 and HepG2.215ΔHBX cells. (E) Western blot analysis of total and phosphorylated AKT in HepG2-NC, HepG2-OEAP1M1, HepG2.215 and HepG2.215-siAP1M1 cells. (F) Cell Counting Kit-8 assay analysis of cell proliferation in HepG2 and HepG2.215 cells treated with or without LY294002. *P<0.05, **P<0.01 and ***P<0.001. HBV, hepatitis B virus; p-AKT, phosphorylated protein kinase B; NC, negative control; si, small interfering.
Figure 3. HBX facilitates AP1M1 expression in liver cancer cells. (A) HBX mRNA was detected by reverse transcription-PCR. (B) AP1M1 protein expression analysis by western blotting of HepG2-NC, HepG2-HBX, HepG2.215 and HepG2.215ΔHBX cells. (C) Quantitative PCR analysis of AP1M1 transcription in HepG2-NC, HepG2-HBX, HepG2.215 and HepG2.215ΔHBX cells. (D) Dual luciferase assay analysis of AP1M1 promoter activity in HepG2-NC, HepG2-HBX, HepG2.215 and HepG2.215ΔHBX cells. (E) Western blot analysis of total and phosphorylated AKT in HepG2-NC, HepG2-OEAP1M1, HepG2.215 and HepG2.215-siAP1M1 cells. (F) Cell Counting Kit-8 assay analysis of cell proliferation in HepG2 and HepG2.215 cells treated with or without LY294002. *P<0.05, **P<0.01 and ***P<0.001. HBV, hepatitis B virus; p-AKT, phosphorylated protein kinase B; NC, negative control; si, small interfering.CC BY-NC-ND · PubMed Central
Figure 4. HBV upregulated AP1M1 expression in a JNK-dependent manner. (A) The transcription factor binding sites were scanned using the JASPAR online software. (B) Analysis of AP1M1 levels from HepG2 and HepG2.215 cells treated with BAY11-7082 by quantitative PCR. (C) Western blot analysis of total and phosphorylated JNK in HepG2 and HepG2.215 treated with or without Sp600125. (D) Quantitative PCR analysis of AP1M1 transcription in HepG2 and HepG2.215 cells treated with Sp600125. (E) AP1M1 protein expression analysis by western blotting. The samples were derived from HepG2 and HepG2.215 cells treated with or without Sp600125. *P<0.05 and **P<0.01. NF, nuclear factor; HBV, hepatitis B virus; p-JNK, phosphorylated C-Jun N-terminal kinase; UTR, untranslated region.
Figure 4. HBV upregulated AP1M1 expression in a JNK-dependent manner. (A) The transcription factor binding sites were scanned using the JASPAR online software. (B) Analysis of AP1M1 levels from HepG2 and HepG2.215 cells treated with BAY11-7082 by quantitative PCR. (C) Western blot analysis of total and phosphorylated JNK in HepG2 and HepG2.215 treated with or without Sp600125. (D) Quantitative PCR analysis of AP1M1 transcription in HepG2 and HepG2.215 cells treated with Sp600125. (E) AP1M1 protein expression analysis by western blotting. The samples were derived from HepG2 and HepG2.215 cells treated with or without Sp600125. *P<0.05 and **P<0.01. NF, nuclear factor; HBV, hepatitis B virus; p-JNK, phosphorylated C-Jun N-terminal kinase; UTR, untranslated region.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Kou, Y., Yan, X., Liu, Q., Wei, X., Zhang, B., Li, X., Pan, W., Kong, F., Wang, Y., Zheng, K., & Tang, R.
Affiliations
  • Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
  • Institute of Emergency and Rescue Medicine, Laboratory of Emergency Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
Venue
Oncology Letters
Publisher
Spandidos Publications
Published
2019-04-30
ISSN
  • 1792-1074
  • 1792-1082
DOI
10.3892/ol.2019.10291
PMC
PMC6540315
Cited by
5
References
44

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