背景：硫氧还蛋白 1 (Trx-1) 是一种主要位于细胞质中的小型氧化还原蛋白。它的表达在多种癌症中增加，包括结直肠癌（CRC）。然而，Trx-1 易位至细胞核在癌症中的功能尚不清楚。在这项研究中，我们研究了 Trx-1 核易位在 CRC 发展中的作用。方法：通过Western blot和免疫荧光分析Trx-1和STAT3的表达。通过免疫共沉淀分析 CRC 细胞中 Trx-1、STAT3 和核传递蛋白 α1 的内源性相互作用。通过免疫组织化学分析人 CRC 组织中的 Trx-1 和 pSTAT3 核染色。利用 AOM/DSS 诱导的结肠炎相关癌症 (CAC) 小鼠模型来研究 Trx-1 抑制剂 PX-12 的抗肿瘤作用。通过 CRISPR/Cas9 产生具有 Txn1(KK81-82EE) 突变的敲入小鼠，并在敲入小鼠和野生型小鼠中诱导 CAC。结果：IL-6诱导Trx-1的核转位，抑制这种转位可逆转IL-6诱导的上皮间质转化、侵袭和转移。人们发现核转运蛋白 α1 特异性介导 IL-6 诱导的 Trx-1-pSTAT3 复合物易位至细胞核中。核Trx-1表达与人类结直肠癌的淋巴结转移和远处转移密切相关。此外，人结直肠癌组织中Trx-1的核染色与pSTAT3的核染色呈显着正相关。 PX-12 是 Trx-1 的抑制剂，可显着损害 STAT3 的激活并抑制 AOM/DSS 诱导的小鼠 CAC 的发展。此外，在 Txn1(KK81-82EE) 小鼠中，AOM/DSS 诱导的核 Trx-1 表达受到抑制，从而抑制 STAT3 激活和癌症进展。结论：这些结果为 IL-6 触发的 STAT3 激活机制提供了新的见解，并将 Trx-1 的核转位确定为治疗 CRC 和 CAC 的潜在治疗靶点。© 作者。

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.© The author(s).