Department of Clinical Medical Research Center, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, PR China.
Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, Guangdong, PR China.
Signal Transduct Target Ther. 2021 Jul 5;6(1):250. doi: 10.1038/s41392-021-00652-x.
Triple-negative breast cancer (TNBC) is the most challenging subtype of breast cancer. Various endeavor has been made to explore the molecular biology basis of TNBC. Herein, we reported a novel function of factor Kinectin 1 (KTN1) as a carcinogenic promoter in TNBC. KTN1 expression in TNBC was increased compared with adjacent tissues or luminal or Her2 subtypes of breast cancer, and TNBC patients with high KTN1 expression have poor prognosis. In functional studies, knockdown of KTN1 inhibited the proliferation and invasiveness of TNBC both in vitro and in vivo, while overexpression of KTN1 promoted cancer cell proliferation and invasiveness. RNA-seq analysis revealed that the interaction of cytokine-cytokine receptor, particularly CXCL8 gene, was upregulated by KTN1, which was supported by the further experiments. CXCL8 depletion inhibited the tumorigenesis and progression of TNBC. Additionally, rescue experiments validated that KTN1-mediated cell growth acceleration in TNBC was dependent on CXCL8 both in vitro and in vivo. Furthermore, it was found that KTN1 enhanced the phosphorylation of NF-κB/p65 protein at Ser536 site, and specifically bound to NF-κB/p65 protein in the nucleus and cytoplasm of cells. Moreover, the transcription of CXCL8 gene was directly upregulated by the complex of KTN1 and NF-κB/p65 protein. Taken together, our results elucidated a novel mechanism of KTN1 gene in TNBC tumorigenesis and progression. KTN1 may be a potential molecular target for the development of TNBC treatment.
三阴性乳腺癌（TNBC）是乳腺癌最具挑战性的亚型。人们已经做出了各种努力来探索 TNBC 的分子生物学基础。在此，我们报道了因子 Kinectin 1（KTN1）作为 TNBC 致癌促进因子的新功能。与相邻组织或管腔或 Her2 型乳腺癌相比，TNBC 中 KTN1 的表达增加，并且 KTN1 高表达的 TNBC 患者预后不良。在功能研究中，KTN1 的敲低抑制了 TNBC 在体外和体内的增殖和侵袭性，而过表达 KTN1 则促进了癌细胞的增殖和侵袭性。RNA-seq 分析显示，细胞因子-细胞因子受体的相互作用，特别是 CXCL8 基因，被 KTN1 上调，进一步的实验支持了这一结果。CXCL8 的缺失抑制了 TNBC 的肿瘤发生和进展。此外，挽救实验验证了 KTN1 在 TNBC 中介导的细胞生长加速依赖于 CXCL8 无论是在体外还是体内。此外，还发现 KTN1 增强了 NF-κB/p65 蛋白在 Ser536 位点的磷酸化，并且在细胞的核和细胞质中特异性结合 NF-κB/p65 蛋白。此外，CXCL8 基因的转录被 KTN1 和 NF-κB/p65 蛋白复合物直接上调。总之，我们的结果阐明了 KTN1 基因在 TNBC 肿瘤发生和进展中的新机制。KTN1 可能是开发 TNBC 治疗方法的潜在分子靶标。
