Liu Xiaorong, Zhou Yehui, Qin Chenglin, Zhu Xun
Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China.
Department of General Surgery, The Second Affiliated Hospital of Jiaxing University, No. 1518 North Huancheng Road, Jiaxing 314000, Zhejiang, China.
J Oncol. 2022 Jun 28;2022:8549781. doi: 10.1155/2022/8549781. eCollection 2022.
Worldwide, breast cancer is the most common cancer in females. Endocrine therapy can effectively treat 85% of breast cancer patients, but 15% of patients could only be treated with chemotherapy and surgery, and the prognosis is much worse. Immunotherapy is the novel treatment for breast cancer, where PD-1 and CTLA-4 antibodies have shown evidence of immune modulation in breast cancer drug trials. In this study, we report that TNFRSF9 regulates the cell proliferation, invasion, and apoptosis of breast cancer cells through regulating the phosphorylation of p38, thus further regulating the expression of PAX6. In both breast cancer tissues and cell lines, the levels of TNFRSF9 are significantly decreased, and breast cancer cell development will be promoted with knockdown of TNFRSF9. Moreover, we identify that downregulation of TNFRSF9 can upregulate the phosphorylated p38 (p-p38) and PAX6. We further elucidate that p-p38 is essential for PAX6 expression as p38 phosphorylation inhibitor can reverse the upregulation of PAX6 and suppress cell proliferation and invasion and promote apoptosis in breast cancer cells. In summary, this study proposed a novel TNFRSF9/p38/PAX6 axis that contributes to tumor suppression, which suggests a potential immunotherapy target for breast cancer.
在全球范围内，乳腺癌是女性中最常见的癌症。内分泌疗法可有效治疗85%的乳腺癌患者，但15%的患者只能接受化疗和手术治疗，且预后要差得多。免疫疗法是乳腺癌的新型治疗方法，在乳腺癌药物试验中，PD - 1和CTLA - 4抗体已显示出免疫调节的证据。在本研究中，我们报告TNFRSF9通过调节p38的磷酸化来调节乳腺癌细胞的增殖、侵袭和凋亡，从而进一步调节PAX6的表达。在乳腺癌组织和细胞系中，TNFRSF9的水平均显著降低，敲低TNFRSF9会促进乳腺癌细胞的发育。此外，我们发现TNFRSF9的下调可上调磷酸化p38（p - p38）和PAX6。我们进一步阐明，p - p38对于PAX6的表达至关重要，因为p38磷酸化抑制剂可逆转PAX6的上调，并抑制乳腺癌细胞的增殖和侵袭，促进其凋亡。总之，本研究提出了一种新的有助于肿瘤抑制的TNFRSF9/p38/PAX6轴，这提示了一种潜在的乳腺癌免疫治疗靶点。
