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J Carcinog. 2018 Jul 23;17:3. doi: 10.4103/jcar.JCar_4_18. eCollection 2018.

Genetic inhibition of autophagy in a transgenic mouse model of anal cancer.

Author information

1
Department of Surgery, University of Wisconsin, WI, USA.
2
Department of Pathology and Laboratory Medicine, University of Wisconsin, WI, USA.
3
William S. Middleton Memorial Veterans Hospital, University of Wisconsin, WI, USA.
4
Carbone Cancer Center, University of Wisconsin, WI, USA.

Abstract

BACKGROUND:

The dynamic role of autophagy in cancer development is a topic of considerable research and debate. Previously published studies have shown that anal cancer development can be promoted or prevented with the pharmacologic inhibition or induction, respectively, of autophagy in a human papillomavirus (HPV) mouse model. However, these results are confounded by the fact that the drugs utilized are known to affect other pathways besides autophagy. It has also been shown that autophagic inhibition occurs in the setting of HPV16 oncoprotein expression (E6 and E7) and correlates with increased susceptibility to anal carcinogenesis.

MATERIALS AND METHODS:

In this study, we employed a conditional, genetic, autophagic (Atg7) knockout mouse model to determine conclusively that autophagy has a role in anal cancer development, in the absence or presence of E6 and E7.

RESULTS:

In mice lacking both HPV16 oncogenes, knockout of autophagy followed by exposure to a carcinogen resulted in a tumor incidence of 40%, compared to 0% in mice treated with a carcinogen alone with an intact autophagic pathway (P = 0.007). In mice expressing either one or both HPV16 oncoproteins, the addition of genetic knockout of autophagy to carcinogen treatment did not lead to a significant difference in tumor incidence compared to carcinogen treatment alone, consistent with the ability of HPV oncogenes to inhibit autophagy in themselves.

CONCLUSIONS:

These results provide the first conclusive evidence for the distinct role of autophagy in anal carcinogenesis, and suggest that autophagy is a plausible target for therapies aimed at reducing anal dysplasia and anal cancer development.

KEYWORDS:

Anal cancer; autophagy; carcinogenesis; human papillomavirus

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