Dysregulation of Autophagy Contributes to Anal Carcinogenesis

Autophagy is an intracellular catabolic process that removes and recycles unnecessary/dysfunctional cellular components, contributing to cellular health and survival. Autophagy is a highly regulated cellular process that responds to several intracellular signals, many of which are deregulated by hum...

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Published in:	PloS one 2016-10, Vol.11 (10), p.e0164273
Main Authors:	Carchman, Evie H, Matkowskyj, Kristina A, Meske, Louise, Lambert, Paul F
Format:	Article
Language:	eng
Subjects:	9,10-Dimethyl-1,2-benzanthracene 9,10-Dimethyl-1,2-benzanthracene - adverse effects Analysis Animals Anthracene Anus Anus Neoplasms - chemically induced Anus Neoplasms - metabolism Anus Neoplasms - pathology Anus Neoplasms - virology Autophagy Biology and Life Sciences Cancer Carcinogenesis Carcinogens Carcinoma, Squamous Cell - chemically induced Carcinoma, Squamous Cell - metabolism Carcinoma, Squamous Cell - pathology Carcinoma, Squamous Cell - virology Cell death Cell survival Cervical cancer Chloroquine Coding Correlation Deregulation Development and progression Drug resistance Dysplasia Electron microscopy Gene Expression Regulation, Neoplastic Genetic engineering Health aspects HIV Human immunodeficiency virus Human papillomavirus Human papillomavirus 16 - genetics Human papillomavirus 16 - metabolism Human papillomavirus 16 - pathogenicity Humans Immunofluorescence Infection Infections Inhibition Intracellular Invasiveness Kinases Lentivirus Medicine and Health Sciences Mice Mice, Transgenic Microtubule-Associated Proteins - metabolism Oncogene Proteins, Viral - genetics Oncogene Proteins, Viral - metabolism p62 Protein Papillomaviridae Papillomavirus E7 Proteins - genetics Papillomavirus E7 Proteins - metabolism Papillomavirus infections Papillomavirus Infections - metabolism Papillomavirus Infections - pathology Phagocytosis Phagosomes Pharmacology Proteins Research and Analysis Methods Retroviridae RNA-Binding Proteins - metabolism Rodents Senescence Squamous cell carcinoma Surgery Transgenic mice Tumors Virology
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Summary:	Autophagy is an intracellular catabolic process that removes and recycles unnecessary/dysfunctional cellular components, contributing to cellular health and survival. Autophagy is a highly regulated cellular process that responds to several intracellular signals, many of which are deregulated by human papillomavirus (HPV) infection through the expression of HPV-encoded oncoproteins. This adaptive inhibitory response helps prevent viral clearance. A strong correlation remains between HPV infection and the development of squamous cell carcinoma (SCC) of the anus, particularly in HIV positive and other immunosuppressed patients. We hypothesize that autophagy is inhibited by HPV-encoded oncoproteins thereby promoting anal carcinogenesis (Fig 1). HPV16 transgenic mice (K14E6/E7) and non-transgenic mice (FVB/N), both of which do not spontaneously develop anal tumors, were treated topically with the chemical carcinogen, 7,12-Dimethylbenz[a]anthracene (DMBA), to induce anal cancer. The anuses at different time points of treatment (5, 10, 15 and 20 weeks) were analyzed using immunofluorescence (IF) for two key autophagy marker proteins (LC3β and p62) in addition to histological grading. The anuses from the K14E6/E7 mice were also analyzed for visual evidence of autophagic activity by electron microscopy (EM). To see if there was a correlation to humans, archival anal specimens were assessed histologically for grade of dysplasia and then analyzed for LC3β and p62 protein content. To more directly examine the effect of autophagic inhibition on anal carcinogenesis, nontransgenic mice that do not develop anal cancer with DMBA treatment were treated with a known pharmacologic inhibitor of autophagy, chloroquine, and examined for tumor development and analyzed by IF for autophagic proteins. Histologically, we observed the progression of normal anoderm to invasive SCC with DMBA treatment in K14E6/E7 mice but not in nontransgenic, syngeneic FVB/N background control mice. With the development of low-grade dysplasia in the K14E6/E7 mice, there was an increase in both punctate LC3β and p62 expression while EM revealed increased autophagosomes without evidence of autophagolysosomes. These observations are consistent with autophagy being inhibited at a later stage in the autophagic process. In contrast, in high-grade dysplasia and SCC in the DMBA-treated K14E6/E7 mice, there were decreased levels of p62 with a continued increase in punctate LC3β expression by IF, while autophag
ISSN:	1932-6203 1932-6203