Format

Send to

Choose Destination
Theranostics. 2018 Apr 30;8(11):3022-3037. doi: 10.7150/thno.23046. eCollection 2018.

PIAS3-mediated feedback loops promote chronic colitis-associated malignant transformation.

Author information

1
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210046, China.
2
Department of General Surgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, China.
3
State Key Laboratory of Analytical Chemistry for Life Sciences and Collaborative Innovation Center of Chemistry for Life Sciences, Nanjing University, Nanjing, Jiangsu 210046, China.

Abstract

Rationale: Colitis-associated colorectal cancer (CAC) usually exhibits an accelerated disease progression, an increased resistance to therapeutic drugs and a higher mortality rate than sporadic colorectal cancer (CRC). PIAS3 is a member of the protein inhibitor of activated STAT (PIAS) family; however, little is known about the expression and biological functions of PIAS3 in CAC. The aim of our study was to investigate the biological mechanisms of PIAS3 in CAC. Methods: PIAS3 expression was examined in colon tissues of CAC/CRC patients and azoxymethane-dextran sulfate sodium (AOM-DSS)-induced mice. The role of PIAS3 was studied using a series of in vitro, in vivo and clinical approaches. Results: Downregulated PIAS3 expression, upregulated miR-18a expression and highly activated NF-κB and STAT3 were observed in colon tissues of CAC/CRC patients and AOM-DSS-induced mice. In vitro experiments revealed that PIAS3 significantly inhibited the activation of NF-κB and STAT3 and demonstrated that activated NF-κB and STAT3 transcriptionally regulated miR-18a level, and up-regulation of miR-18a expression led to defective PIAS3 expression. Moreover, PIAS3-mediated autoregulatory feedback loops (PIAS3/NF-κB/miR-18a and PIAS3/STAT3/miR-18a) were verified in vitro and were found to regulate cell proliferation. Additionally, modulation of the feedback loops via overexpression of PIAS3 or knockdown of miR-18a significantly inhibited cell proliferation in a mouse CRC xenograft model. Furthermore, upregulation of PIAS3 by intracolonic administration of PIAS3 lentivirus or anti-miR-18a lentivirus in AOM-DSS-induced mice led to dramatically reduced tumor sizes/numbers, whereas knockdown of PIAS3 in CAC mice significantly promoted tumor growth. Conclusion: Our data clearly show that PIAS3-mediated feedback loops control cell proliferation and function as robust driving forces for CAC progression. Targeting these highly activated feedback loops might offer promising therapeutic strategies for CAC.

KEYWORDS:

NF-κB; PIAS3; STAT3; colitis-associated colorectal cancer; miR-18a

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Supplemental Content

Full text links

Icon for Ivyspring International Publisher Icon for PubMed Central
Loading ...
Support Center