Human papillomavirus infection and expression of ATPase family AAA domain containing 3A, a novel anti-autophagy factor, in uterine cervical cancer

Abstract

Abstract. Our aim was to determine the association of human papillomavirus (HPV) infection with the expression of ATPase family AAA domain containing 3A (ATAD3A), an anti-autophagy factor, in uterine cervical cancer (UCC). The HPV genotype was determined by an Easychip HPV blot assay. ATAD3A expression was determined by immunohistochemical staining. High-risk HPV (hrHPV) was detected in 184 (88.9%) of 207 UCC cases. ATAD3A expression was detected in 164 (79.2%) UCC cases. A significant correlation was found between ATAD3A expression and the presence of hrHPV (p<0.001), FIGO stage (p=0.014), lymph node involvement (p=0.001), c-MET expression (p<0.001), interleukin-8 (p=0.03) and patient survival (p=0.0016). Interestingly, silencing of E6/E7 expression decreased ATAD3A expression and cell survival. Moreover, knockdown of ATAD3A (ATAD3A kd ) expression or addition of resveratrol, increased cellular autophagy and apoptosis and reduced drug resistance. Resveratrol reduced ATAD3A expression, and increased abrasion of the mitochondrial outer membrane as well as numbers of autophagosomes, the phenomena that were frequently found in ATAD3A kd cells. In conclusion, our results show that HPV infection correlates with increased ATAD3A expression and drug resistance in UCC. Persistent HPV infection may stabilize ATAD3A expression to inhibit cell autophagy and apoptosis as well as to increase drug resistance. IntroductionUterine cervical cancer (UCC) is the most prevalent cancer, and the fifth leading cause of cancer-related deaths in Taiwanese women (1). High incidence and mortality of the disease was in part due to the conservative attitude toward the Papanicolaou smear, because even though the disease could be detected at the early stages the method was considered intrusive, and in part due to the high infection rate of human papillomavirus (HPV) among the diseased women (2). HPV infection is a potential etiologic cause for UCC development (3,4). Among 95 known HPV (5), genotypes 16, 18, 52 and 58 are categorized as high-risk and most frequently detected in Taiwanese UCC patients (6-9). Carcinogenicity of the high-risk HPV (hrHRV) is closely associated with E6 and E7 proteins, which can respectively inhibit activities of tumor suppressors, p53 and retinoblastoma protein (pRB), to interrupt cell growth regulation (10). Besides carcinogenesis, persistent HPV infection further correlates with tumor recurrence, cancer cell radiosensitivity and the resulting poor prognosis (11-13).Oncogene activation is also crucial for tumorigenesis and cancer progression; in particular, genes that are associated with disease advancement and, possibly, resistance to irradiation and anticancer chemotherapeutics. By using differential display, we have identified overexpression of dihydrodiol dehydrogenase (DDH) in non-small cell lung cancer (14). Using microarrays, we further found that DDH was overexpressed in cisplatin-resistant ovarian cancer cells (15). Clinically, patients with elevated DDH have a higher tumor recurrence rate and lymph node...

Baculovirus LEF-11 Hijack Host ATPase ATAD3A to Promote Virus Multiplication in Bombyx mori cells

“…In this study, results demonstrated that ATAD3A expression was closely associated with BmNPV infection similar with a previously reported study on HPV infection (Fig. S2C)38. Interestingly, additional results demonstrated that overexpression of ATAD3A promotes virus multiplication in the Bombyx mori cells (Fig.…”

“…3). These results further explain why this protein expression correlates with virus infection and cancer in the mammalian cells3839. According to the phenomenon that propagation and replication of baculovirus would be inhibited through integrating silencing ATAD3A with the experimental results mentioned above, we speculate that virus could use ATAD3A to utilize host factor energy for their replication (Fig.…”

ATAD3, a vital membrane bound mitochondrial ATPase involved in tumor progression

“…Thus, ATAD3B is a putative marker which could enable the discrimination of oligodendroglioma from astrocytoma and surrounding healthy tissue (Hubstenberger et al 2008). More recently and confirming these results, it has been shown that ATAD3A constitutes an anti-apoptotic marker in lung tumors (Fang et al 2010) and a radioresistance marker in non-Hodgkin lymphoma and uterine cervical cancer (Jiang et al 2009;Chen et al 2011).…”

Reduced expression of autophagy markers correlates with high-risk human papillomavirus infection in human cervical squamous cell carcinoma

“…It is hypothesized that the HPV-host cell interaction stimulates the PI3K/Akt/mTOR pathway and inhibits autophagy, and in combination these events aid virus infection (36). In addition, persistent HPV infection may stabilize the ATPase family AAA domain containing 3A (an anti-autophagy factor) expression to inhibit cell autophagy and apoptosis, as well as increasing drug resistance in uterine cervical cancer (37). Simultaneously, the clinicopathological significance of negative Beclin-1 and LC3B expression in cervical SCC with hrHPV infection was investigated, and the results revealed that negative expression of Beclin-1 and LC3B in cervical SCC with hrHPV infection promoted a higher clinical TNM stage and lymph node metastasis, indicating that the absence of autophagy combined with hrHPV infection may accelerate cervical SCC progression.…”