Inhibition of apoptosis by oncogenic hepatitis B virus X protein: Implications for the treatment of hepatocellular carcinoma

Abstract

Hepatitis B virus X protein (HBx) plays an important role in the development of hepatocellular carcinoma (HCC). In addition, hepatoma upregulated protein (HURP) is a cellular oncogene that is upregulated in a majority of HCC cases. We highlight here recent findings demonstrating a link between HBx, HURP and anti-apoptosis effects observed in cisplatin-treated HCC cells. We observed that Hep3B cells overexpressing HBx display increased HURP mRNA and protein levels, and show resistance to cisplatin-induced apoptosis. Knockdown of HURP in HBx-expressing cells reverses this effect, and sensitizes cells to cisplatin. The anti-apoptotic effect of HBx requires activation of the p38/MAPK pathway as well as expression of SATB1, survivin and HURP. Furthermore, silencing of HURP using short-hairpin RNA promotes accumulation of p53 and reduces cell proliferation in SK-Hep-1 cells (p53 +/-), whereas these effects are not observed in p53-mutant Mahlavu cells. Similarly, HURP silencing does not affect the proliferation of H1299 lung carcinoma cells or Hep3B HCC cells which lack p53. Silencing of HURP sensitizes SK-Hep-1 cells to cisplatin. While HURP overexpression promotes p53 ubiquitination and degradation by the proteasome, HURP silencing reverses these effects. Inoculation of SK-Hep-1 cancer cells in which HURP has been silenced produces smaller tumors than control in nude mice. Besides, gankyrin, a positive regulator of the E3 ubiquitin ligase MDM2, is upregulated following HURP expression, and silencing of gankyrin reduces HURP-mediated downregulation of p53. In addition, we observed a positive correlation between HURP and gankyrin protein levels in HCC patients (r 2 = 0.778; n = 9). These findings suggest a role for the viral protein HBx and the host protein HURP in preventing p53-mediated apoptosis during cancer progression and establishment of chemoresistance. Core tip: Hepatitis B virus X protein (HBx) plays a critical role in the development of hepatocellular carcinoma (HCC). Hepatoma upregulated protein (HURP) is an oncogene that is upregulated in a majority of HCC cases. However, the role of these proteins in the response of HCC cells to chemotherapeutic drugs remains unclear. We show here that the HBx/SATB1/HURP axis plays a critical role in down-regulating p53 and upregulating anti-apoptotic proteins in vitro and in vivo . We discuss the regulation of this novel pathway and its implications in resistance of HCC cells to chemotherapy.Chao CCK. Inhibition of apoptosis by oncogenic hepatitis B virus X protein: Implications for the treatment of hepatocellular carcinoma.

Hepatitis B Spliced Protein (HBSP) Suppresses Fas-Mediated Hepatocyte Apoptosis via Activation of PI3K/Akt Signaling

“…A large body of studies have been performed by the investigators in the field trying to determine the relationship of HBV infection and apoptosis; however, the results are still in controversy. HBV or HBx is generally believed to inhibit cellular apoptosis, thereby facilitating virus proliferation and promoting HCC progression (12,(47)(48)(49). However, the fact that HBV infection could induce apoptosis has also been reported in several studies (17,20,50).…”

Viral Infections: Negative Regulators of Apoptosis and Oncogenic Factors

“…In addition, HBx enhances expression of the N-terminal isoforms of p73, which is a trans-dominant inhibitor of p53 [ 21 ]. Also, HBx has been shown to enhance expression level of HURP (hepatoma upregulated protein), which promotes p53 degradation and suppression of apoptosis induced by chemotherapeutic DNA damaging agents [ 22 ]. Thus, reactivation of hepatitis B virus, which is often observed as a result of therapy for hematologic malignancies, breast cancer, and other malignant tumors, diminishes response to the treatment [ 23 ].…”

Interference of Apoptosis by Hepatitis B Virus

“…Plenty of studies have been performed to determine the relationship of HBV infection and apoptosis, but the results are still contradictory. The majority of the papers showed that HBV or HBX could inhibit the cellular apoptosis, thereby facilitating the virus proliferation and promoting the HCC progression [ 61 , 62 , 63 ]. Various studies have been done to define the balance among the HBV proliferation, apoptosis and HCC.…”