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Abstract
Epstein-Barr virus (EBV) and human papillomavirus (HPV) infection is the risk factors for nasopharyngeal carcinoma and cervical carcinoma, respectively. However, clinical analyses demonstrate that EBV or HPV is associated with improved response of patients, although underlying mechanism remains unclear. Here, we reported that the oncoproteins of DNA viruses, such as LMP1 of EBV and E7 of HPV, inhibit PERK activity in cancer cells via the interaction of the viral oncoproteins with PERK through a conserved motif. Inhibition of PERK led to increased level of reactive oxygen species (ROS) that promoted tumor and enhanced the efficacy of chemotherapy in vivo. Consistently, disruption of viral oncoprotein-PERK interactions attenuated tumor growth and chemotherapy in both cancer cells and tumor-bearing mouse models. Our findings uncovered a paradoxical effect of DNA tumor virus oncoproteins on tumors and highlighted that targeting PERK might be an attractive strategy for the treatment of NPC and cervical carcinoma.
Highlights
12% of human cancers worldwide are caused by oncovirus infection
DNA tumor virus oncogenes regulate PERK signaling Epstein-Barr virus (EBV) can persistently infect and transform human cells, which induces the development of several types of cancers, such as nasopharyngeal carcinoma (NPC), lymphomas and gastric carcinomas
Given that oncoprotein latent membrane protein 1 (LMP1) is essential for the ability of EBV to immortalize human cells, we speculated that LMP1 may be involved in regulation of unfolded protein response (UPR)
Summary
Despite the prevalence of oncoviruses, understanding and managing virus-induced cancers still face formidable challenges.[1,2] DNA tumor viruses, such as Epstein-Barr virus (EBV) and human papillomavirus (HPV), are an important class of oncoviruses that can integrate into the patient genome, resulting in tumorigenesis.[3] Mechanistically, oncoproteins, such as latent membrane protein 1 (LMP1) encoded by EBV, can transform cells via activation of nuclear factor κB (NF-κB) signaling, leading to nasopharyngeal carcinoma (NPC), Burkitt’s lymphoma, Hodgkin’s lymphomas and gastric carcinomas.[4] The E6 and E7 oncoproteins encoded by HPV transform cells by inhibiting the functions of p53 and Rb, giving rise to the development of cervical, anal, and skin cancers.[3] Surprisingly, DNA tumor viruses have strong transforming abilities that can promote cancer progression, patients with DNA tumor virus-positive cancer, including HPV-positive cervical cancer and EBV-positive gastric adenocarcinoma or classical Hodgkin lymphoma (cHL), have a better prognosis than patients with virus-negative cancer.[5,6,7,8] To date, the underlying mechanism has not been elucidated. The PERK-mediated UPR, as a key mediator in the response to stress stimuli, can facilitate or suppress malignant transformation depending on the context.[12,13,14,15,16]
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