Ras/MAPK Pathway in Viral Associated Cancers

Viruses account for around ۱۲ to ۲۰ percent of cancers affecting humans globally, with seven viruses—hepatitis C virus (HCV), hepatitis B virus (HBV), human papillomavirus (HPV), Epstein-Barr virus (EBV), human T-cell leukemia virus type ۱ (HTLV-۱), Merkel cell polyomavirus (MCPyV), and Kaposi’s sarcoma-associated herpesvirus (KSHV)—being directly implicated in tumorigenesis. These oncoviruses target the Ras/MAPK signaling pathway, which is a pivotal regulator of key cell processes such as growth, differentiation, and programmed cell death. Dysregulated activation of the Ras/MAPK pathway is a major driver of cancer development, progression, and sustenance. By hijacking this pathway, oncoviruses drive tumorigenesis through mechanisms such as upregulating growth factor receptors, inducing angiogenesis, and promoting invasion and metastasis. They also induce the MAPK/ERK pathway by downregulating tumor suppressors, creating a pro-oncogenic environment. For example, HPV infects cells by binding to heparan sulfate proteoglycans and entering via endocytosis. The integration of viral DNA into the host genome leads to the overexpression of E۶ and E۷ oncoproteins. These proteins degrade the tumor suppressors p۵۳ and pRb, respectively, disrupting cellular safeguards and promoting tumorigenesis. Blocking the E۶-p۵۳ and E۷-pRb complexes could be a promising strategy to suppress viral infections and halt cancer progression. Similarly, in HTLV-۱-associated adult T-cell leukemia, the Tax۱ oncoprotein increases Ras-GTP levels and ERK phosphorylation, promoting an anti-apoptotic state that facilitates viral replication. Targeting this pathway with agents like Ras farnesylcysteine mimetics has demonstrated potential in restoring apoptosis sensitivity. Therefore, understanding these mechanisms provides critical insights into therapeutic targets for virus-associated cancers. Further research into these interactions is essential for developing effective therapies to combat these malignancies.

کلیدواژه ها:

Cancer ، ERK ، MAPK ، Oncoviruses ، RasIntroduction