NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, 130 Dong'an Road, Xuhui District, Shanghai, 200032, China.
Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, 270 Dong'an Road, Xuhui District, Shanghai, 200032, China.
Oncogene. 2022 Oct;41(41):4658-4672. doi: 10.1038/s41388-022-02459-8. Epub 2022 Sep 10.
Metastasis of breast cancer represents the major reason for its poor prognosis, leading to high mortality. In breast cancer, a tumor suppressor gene TP53 is commonly mutated. TP53 mutation leads to an altered expression of various genes, an event that is associated with aggressive tumor and is a strong independent marker for survival. In this study, we identified a novel p53 target gene, immunoglobulin superfamily 9 (IGSF9). IGSF9 is generally down-regulated in breast cancer tissues. Loss of IGSF9 is associated with frequent metastasis and poor prognosis of breast cancer patients. Wild-type p53, but not R175H mutant, trans-activates the transcription of IGSF9 via binding to its promoter (-137 to -131 bp), inhibits epithelial-mesenchymal transition (EMT), consequently the inhibition of breast cancer cells migration and invasion. IGSF9 interacts with focal adhesion kinase (FAK) and inhibits FAK/AKT signaling activity. PND1186, FAK inhibitor, inhibits breast cancer metastasis induced by IGSF9 knockdown in vitro and in vivo. Taken together, IGSF9 is trans-activated by p53 and inhibits breast cancer metastasis by modulating FAK/AKT signaling pathway. IGSF9 could serve as a prognostic marker and potential therapeutic target for breast cancer.
乳腺癌的转移是其预后不良的主要原因，导致死亡率较高。在乳腺癌中，肿瘤抑制基因 TP53 通常发生突变。TP53 突变导致各种基因的表达改变，这种事件与侵袭性肿瘤相关，是生存的一个强有力的独立标志物。在这项研究中，我们鉴定了一个新的 p53 靶基因，免疫球蛋白超家族 9（IGSF9）。IGSF9 在乳腺癌组织中通常下调。IGSF9 的缺失与乳腺癌患者的频繁转移和预后不良有关。野生型 p53 而不是 R175H 突变型通过结合其启动子（-137 至-131bp）来转录激活 IGSF9 的转录，抑制上皮-间充质转化（EMT），从而抑制乳腺癌细胞的迁移和侵袭。IGSF9 与粘着斑激酶（FAK）相互作用并抑制 FAK/AKT 信号活性。FAK 抑制剂 PND1186 抑制 IGSF9 敲低在体外和体内诱导的乳腺癌转移。总之，IGSF9 被 p53 反式激活，并通过调节 FAK/AKT 信号通路抑制乳腺癌转移。IGSF9 可作为乳腺癌的预后标志物和潜在治疗靶点。
