Regulation of Autophagy in Cells Infected With Oncogenic Human Viruses and Its Impact on Cancer Development

Abstract

About 20% of total cancer cases are associated to infections. To date, seven human viruses have been directly linked to cancer development: high-risk human papillomaviruses (hrHPVs), Merkel cell polyomavirus (MCPyV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), and human T-lymphotropic virus 1 (HTLV-1). These viruses impact on several molecular mechanisms in the host cells, often resulting in chronic inflammation, uncontrolled proliferation, and cell death inhibition, and mechanisms, which favor viral life cycle but may indirectly promote tumorigenesis. Recently, the ability of oncogenic viruses to alter autophagy, a catabolic process activated during the innate immune response to infections, is emerging as a key event for the onset of human cancers. Here, we summarize the current understanding of the molecular mechanisms by which human oncogenic viruses regulate autophagy and how this negative regulation impacts on cancer development. Finally, we highlight novel autophagy-related candidates for the treatment of virus-related cancers. Keywords: oncogenic (or carcinogenic) viruses, autopaghy, human papillomavirus (HPV), Merkel cell polyomavirus (MCPyV), hepatitis B and C viruses (HBV and HCV), Epstein-Barr virus (EBV), Kaposi's sarcomaassociated herpesvirus (KSHV), human T-lymphotropic virus 1 (HTLV-1)

Kaposi’s sarcoma-associated herpesvirus (KSHV) utilizes the NDP52/CALCOCO2 selective autophagy receptor to disassemble processing bodies

“…Autophagy plays a dual role in cancer development mediated by oncogenic viruses (Vescovo et al , 2020). Autophagy is initially tumour suppressive, promoting degradation of damaged organelles, preserving genomic stability, and removing pathogens.…”

“…In cancers of viral origin, like KS, viral inhibition of autophagic flux can help control xenophagy of new viral particles and aid in the establishment of latent infection (Jang et al , 2016). However, once cancer is established, autophagic flux promotes progression of established tumours by a variety of approaches, including promoting a pro-tumourigenic and proinflammatory environment (Vescovo et al , 2020; Liu & Debnath, 2016). Consistent with this, markers of upregulated autophagic flux are elevated in several cancers and in primary effusion lymphoma cells that harbour the KSHV genome as a latent episome (Pringle et al, 2019; reviewed in Wu et al, 2012), suggesting that at this latent stage, viral gene products enhance autophagy to maintain tumourigenesis.…”

“…Consistent with this, markers of upregulated autophagic flux are elevated in several cancers and in primary effusion lymphoma cells that harbour the KSHV genome as a latent episome (Pringle et al, 2019; reviewed in Wu et al, 2012), suggesting that at this latent stage, viral gene products enhance autophagy to maintain tumourigenesis. This sensible model is, in reality, an oversimplification, as we know that KSHV gene products both enhance and block autophagic flux during both latent and lytic KSHV phases (Vescovo et al , 2020; Cirone, 2018). In latency, two viral proteins have previously defined roles in autophagy, vCyclin and vFLIP (Leidal et al , 2012; Lee et al , 2009).…”

Canonical and Noncanonical Roles of Fanconi Anemia Proteins: Implications in Cancer Predisposition

“…On the other hand, defects in virophagy cannot be ignored. During viral infections, autophagy is an essential response that could guarantee virus depletion and cell survival [ 156 ]. In Papillomavirus infection, HPV has been reported to inhibit autophagy, thus both avoiding early viral degradation during de novo infection and promoting the malignant transformation of infected cells [ 157 ].…”

Immunopathogenesis and Cellular Interactions in Human T-Cell Leukemia Virus Type 1 Associated Myelopathy/Tropical Spastic Paraparesis

“…HBZ also downregulates apoptosis and autophagy by reducing FoxO3a-mediated transcription of Bim and mTOR inhibitor, respectively. These regulatory functions contribute to cell proliferation, maintenance of viral reservoirs, and cancer development in ATLL ( Mukai and Ohshima, 2014 ; Vescovo et al, 2020 ). Although both Tax and HBZ are transcribed in bursts in a single clone ( Billman et al, 2017 ); HBZ is expressed in most of the infected cells ( Satou et al, 2006 ), whereas Tax expression is silenced in various clones through epigenetic and genetic modifications and other viral regulatory genes such as rex , p30 , and hbz ( Nicot et al, 2004 ; Takeda et al, 2004 ; Taniguchi et al, 2005 ).…”