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


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-?B 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-?B and STAT3 and demonstrated that activated NF-?B 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-?B/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.

SUBMITTER: Ma J 

PROVIDER: S-EPMC5996365 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Ma Junting J   Yang Yaping Y   Fu Yong Y   Guo Feilong F   Zhang Xiaoyi X   Xiao Shuke S   Zhu Weiming W   Huang Zhen Z   Zhang Junfeng J   Chen Jiangning J  

Theranostics 20180430 11


<b>Rationale:</b> 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. <b>Methods:</b> PIAS3 expre  ...[more]

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