The Autophagy Process in Cervical Carcinogenesis: Role of Non-Coding-RNAs, Molecular Mechanisms, and Therapeutic Targets

Abstract

Autophagy is a highly conserved multistep lysosomal degradation process in which cellular components are localized to autophagosomes, which subsequently fuse with lysosomes to degrade the sequestered contents. Autophagy serves to maintain cellular homeostasis. There is a close relationship between autophagy and tumor progression, which provides opportunities for the development of anticancer therapeutics that target the autophagy pathway. In this review, we analyze the effects of human papillomavirus (HPV) E5, E6, and E7 oncoproteins on autophagy processes in cervical cancer development. Inhibition of the expression or the activity of E5, E6, and E7 can induce autophagy in cells expressing HPV oncogenes. Thus, E5, E6, and E7 oncoproteins target autophagy during HPV-associated carcinogenesis. Furthermore, noncoding RNA (ncRNA) expression profiling in cervical cancer has allowed the identification of autophagy-related ncRNAs associated with HPV. Autophagy-related genes are essential drivers of autophagy and are regulated by ncRNAs. We review the existing evidence regarding the role of autophagy-related proteins, the function of HPV E5, E6, and E7 oncoproteins, and the effects of noncoding RNA on autophagy regulation in the setting of cervical carcinogenesis. By characterizing the mechanisms behind the dysregulation of these critical factors and their impact on host cell autophagy, we advance understanding of the relationship between autophagy and progression from HPV infection to cervical cancer, and highlight pathways that can be targeted in preventive and therapeutic strategies against cervical cancer.

Identification and validation of novel biomarker TRIM8 related to cervical cancer

“…Despite the proved role of autophagy in the occurrence and development of cervical cancer ( 18 ), more efforts are required to fill the research blank on the specific mechanism. In this way, more autophagy-related genes and corresponding signal pathways will be available for the diagnosis and treatment of cervical cancer.…”

“…Molecular, epidemiological, and clinical investigations have identified HPV as the main cause ( 25 ). Autophagy is a highly conserved multi-step lysosomal degradation process, in which cellular components are limited to autophagosomes, and then fuse with lysosomes to degrade chelated contents ( 18 ). The close relationship between autophagy and tumor progression is confirmed.…”

HPV16 E6 and E7 are involved in inhibition of autophagy and maintenance of cancer stem cell properties in HPV16‐positive oral squamous cell carcinoma cells

“…10 HPV16 E6/E7 impair the fusion between autophagosome and lysosome in cervical cancers. 10,40 In addition, HPV16 E5 attenuates the transcription of several autophagy-related genes such as ATG5, LC-3, BECN1, ATG7, and ULK1, leading to inhibition of phagophore assembly in cervical cancers. 10,40 These results suggest that HPV16 oncoprotein negatively regulates the autophagy process.…”

“…10,40 In addition, HPV16 E5 attenuates the transcription of several autophagy-related genes such as ATG5, LC-3, BECN1, ATG7, and ULK1, leading to inhibition of phagophore assembly in cervical cancers. 10,40 These results suggest that HPV16 oncoprotein negatively regulates the autophagy process. However, HPV16 E7 alone enhances LC3 puncta formation (i.e., induction of autophagy) in human keratinocytes, suggesting that HPV16 E7 oncoprotein plays a positive role in autophagy regulation.…”

“…8 HPV16 E5 inhibits mRNA expression of autophagy-related genes such as BECN1 and ATG5 in human keratinocytes, 9 whereas high-risk HPV E6/E7 play a vital role in cervical carcinogenesis by suppressing pro-autophagic gene expression. 10 Thus, it is likely that high-risk HPV oncoproteins counteract the autophagy system in human epithelial cells and cervical cancer cells. However, it remains unknown whether HPV E6/E7 is involved in autophagy regulation in oral squamous cell carcinoma (OSCC) cells.…”