结直肠癌（CRC）是一种具有复杂机制的严重疾病，这些机制推动了其增殖和转移。尽管癌症研究取得了重大进展，但对于影响癌细胞行为的这些机制的整合仍然不清楚。因此，全面阐明驱动CRC增殖和转移的潜在机制至关重要。在本研究中，我们报道了SLC26A3在抑制CRC进展中的新角色。我们发现，SLC26A3在CRC中表达下调，与生存率成正比。我们的体内和体外实验证明，SLC26A3的上调抑制了CRC的增殖和转移，而SLC26A3的下调通过调节IκB的表达水平促进了CRC的进展。此外，我们还确定了SLC26A3的一个新的相互作用蛋白NHERF2，它负责稳定IκB蛋白并去除泛素化修饰。机制上，SLC26A3增强了NHERF2与IκB之间的相互作用，随之减少了其降解。这个过程抑制了p65从IκB/p65/p50复合物中的解离，减少了p65从细胞质向细胞核的转位。此外，我们的研究揭示了NF-κB/p65直接结合到SLC26A3的启动子上，导致其mRNA表达下降。因此，SLC26A3阻止了NF-κB/p65的核转位，增强了SLC26A3的转录，建立了CRC细胞中的正向调节反馈环路。总之，这些结果表明SLC26A3/NHERF2-IκB/NF-κB/p65信号环路抑制了CRC细胞的增殖和转移。这些发现提出了一个在CRC中调节增殖和转移的新的SLC26A3驱动信号环路，为CRC的治疗干预和预后靶点提供了希望。© 2023. Springer Nature America, Inc.

Colorectal cancer (CRC) is a formidable disease due to the intricate mechanisms that drive its proliferation and metastasis. Despite significant progress in cancer research, the integration of these mechanisms that influence cancer cell behavior remains elusive. Therefore, it is imperative to comprehensively elucidate the underlying mechanisms driving CRC proliferation and metastasis. In this study, we reported a novel role of SLC26A3 in suppressing CRC progression. We found that SLC26A3 expression was downregulated in CRC, which was proportionally correlated with survival. Our in vivo and in vitro experiments demonstrated that up-regulation of SLC26A3 inhibited CRC proliferation and metastasis, while down-regulation of SLC26A3 promoted CRC progression by modulating the expression level of IκB. Furthermore, we identified NHERF2 as a novel interacting protein of SLC26A3 responsible for stabilizing the IκB protein and removing ubiquitination modification. Mechanistically, SLC26A3 augmented the interaction between NHERF2 and IκB, subsequently reducing its degradation. This process inhibited the dissociation of p65 from the IκB/p65/p50 complex and reduced the translocation of p65 from the cytoplasm to the nucleus. Moreover, our investigation revealed that NF-κB/p65 directly bound to the promoter of SLC26A3, leading to a decline in its mRNA expression. Thus, SLC26A3 impeded the nuclear translocation of NF-κB/p65, enhancing the transcription of SLC26A3 and establishing a positive regulatory feedback loop in CRC cells. Collectively, these results suggest that a SLC26A3/NHERF2-IκB/NF-κB/p65 signaling loop suppresses proliferation and metastasis in CRC cells. These findings propose a novel SLC26A3-driven signaling loop that regulates proliferation and metastasis in CRC, providing promising therapeutic interventions and prognostic targets for the management of CRC.© 2023. Springer Nature America, Inc.