Nuclear translocation of thioredoxin-1 promotes colorectal cancer development via modulation of the IL-6/STAT3 signaling axis through interaction with STAT3

Aihua Wu; Daoquan Fang; Yangyang Liu; Xiaomeng Shi; Zuyue Zhong; Baojian Zhou; Lechi Ye; Xuecheng Sun; Lei Jiang

doi:10.7150/thno.85460

Nuclear translocation of thioredoxin-1 promotes colorectal cancer development via modulation of the IL-6/STAT3 signaling axis through interaction with STAT3

Theranostics. 2023 Aug 28;13(14):4730-4744. doi: 10.7150/thno.85460. eCollection 2023.

Authors

Aihua Wu^{1

2}, Daoquan Fang², Yangyang Liu², Xiaomeng Shi², Zuyue Zhong², Baojian Zhou², Lechi Ye³, Xuecheng Sun⁴, Lei Jiang²

Affiliations

¹ Department of Laboratory Medicine, The First Affiliated Hospital of Ningbo University, Ningbo 315010, China.
² Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
³ Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
⁴ Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.

Abstract

Background: Thioredoxin 1 (Trx-1) is a small redox protein predominantly localized in the cytoplasm. Its expression is increased in several cancers, including colorectal cancer (CRC). However, the function of Trx-1 translocation to the nucleus in cancer is not clear. In this study, we investigated the role of Trx-1 nuclear translocation in development of CRC. Methods: Expression of Trx-1 and STAT3 was analyzed by Western blot and immunofluorescence. Endogenous interaction of Trx-1, STAT3, and karyopherin α1 in CRC cells was analyzed by co-immunoprecipitation. Trx-1 and pSTAT3 nuclear staining in human CRC tissues was analyzed by immunohistochemistry. A mouse model of AOM/DSS induced colitis-associated cancer (CAC) was utilized to investigate the antitumor effect of PX-12, a Trx-1 inhibitor. A knockin mouse with the Txn1(KK81-82EE) mutation was generated via CRISPR/Cas9, and CAC was induced in knockin and wild-type mice. Results: Nuclear translocation of Trx-1 was induced by IL-6, and inhibition of this translocation reversed IL-6-induced epithelial-to-mesenchymal transition, invasion and metastasis. Karyopherin α1 was found to specifically mediate IL-6-induced translocation of the Trx-1-pSTAT3 complex into the nucleus. Nuclear Trx-1 expression was closely correlated with lymph node metastasis and distant metastasis in human CRC. In addition, nuclear staining of Trx-1 showed significant positive correlation with nuclear staining of pSTAT3 in human CRC tissues. PX-12, an inhibitor of Trx-1, significantly impaired the activation of STAT3 and suppressed the development of AOM/DSS-induced CAC in mice. Moreover, AOM/DSS-induced nuclear Trx-1 expression was suppressed in Txn1(KK81-82EE) mice, which inhibited STAT3 activation and cancer progression. Conclusions: These results provide new insights into the mechanisms of STAT3 activation triggered by IL-6 and identify nuclear translocation of Trx-1 as a potential therapeutic target for the treatment of CRC and CAC.

Keywords: Colorectal cancer; IL-6; STAT3; Trx-1; nuclear translocation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Colorectal Neoplasms* / pathology
Humans
Interleukin-6* / metabolism
Mice
STAT3 Transcription Factor / metabolism
Signal Transduction
Thioredoxins* / genetics
Thioredoxins* / metabolism

Substances

Interleukin-6
STAT3 Transcription Factor
Thioredoxins
Txn1 protein, mouse