Abstract
Pancreatic cancer is one of the more common cancers with a poor prognosis. Some varieties of cancer are related to virus infection. As a virus-induced protein, APOBEC3G (A3G) presents extensive anti-virus ability, but the role of A3G in pancreatic cancer was previously unknown. The expression of A3G in pancreatic cancer was examined using TaqMan real-time qPCR, immunohistochemical and immunofluorescent staining. Subsequently, the role of A3G in pancreatic cancer was evaluated in vivo using the tumor xenograft model. Anoikis was detected by colony formation assay and flow cytometry in vitro. The Akt kinase activity and target protein PTEN were examined by co-immunoprecipitation and immunoblot. The virus-induced protein A3G was significantly up-regulated in pancreatic cancer, and the up-regulation of A3G promoted xenograft tumor formation. A3G inactivated PTEN by binding to the C2 tensin-type and PDZ domains, thereby inducing anoikis resistance through Akt activation. Our results demonstrate that the up-regulation of A3G in pancreatic cancer cells induces anoikis resistance, and they provide novel insight into the mechanism by which A3G affects the malignant behavior of pancreatic cancer cells.
Highlights
Pancreatic cancer is the fourth most common cause of cancer-related deaths[1], with a 5-year survival rate of only 1–4%2
We found that A3G induced anoikis resistance through Akt activation, which was allowed by the inactivation of PTEN phosphatase, suggesting that A3G can enhance the malignant behavior of pancreatic cancer in addition to limiting viral replication
We found that two genes of virus-induced proteins, A3G and APOBEC3F (A3F), were significantly enriched in SW620-initiating cells, as determined by a global cDNA expression microarray (Fig. 1B; Supplementary Table S1)
Summary
Pancreatic cancer is the fourth most common cause of cancer-related deaths[1], with a 5-year survival rate of only 1–4%2. Anoikis resistance is an early molecular event in the development of cancer and plays an important role in metastasis[3]. Anoikis is a special form of cell apoptosis induced by disengagement of the cells from the extracellular matrix and from other cells It plays an important role in tissue homeostasis, disease development, and tumor metastasis[4]. Initiating cells residing within tumors are the origin of pancreatic cancer proliferation, metastasis, recurrence, and drug resistance. RNA tumor viruses, known as retroviruses, have promoters or enhancers that are meant to promote the transcription of viral proteins These promoters and enhancers can insert into nearby oncogenes of the host DNA after reverse transcription and induce the activation and overexpression of oncogenes and can lead to cell transformation[15,16,17]. We found that A3G induced anoikis resistance through Akt activation, which was allowed by the inactivation of PTEN phosphatase, suggesting that A3G can enhance the malignant behavior of pancreatic cancer in addition to limiting viral replication
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