Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100, Tzyou 1st Road, Kaohsiung, 807, Taiwan.
Department of Pathology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Hum Cell. 2022 Nov;35(6):1912-1927. doi: 10.1007/s13577-022-00776-4. Epub 2022 Sep 2.
Serine peptidase inhibitor Kazal type-1 (SPINK1), a trypsin kinase inhibitor, is known to be associated with inflammation and pathogenesis. The aim in this study was to demonstrate the clinicopathological role and progression of SPINK1 in rectal cancer (RC) patients undergoing concurrent chemoradiotherapy (CCRT). Immunohistochemical staining for SPINK1 protein expression in 111 RC cases revealed high SPINK1 expression was significantly associated with perineural invasion and poor CCRT response in pre-CCRT specimens. In addition, multivariable analyses showed that pre-CCRT SPINK1 expression was a significant prognostic marker of both overall and disease-free survival in RC patients receiving pre-operative CCRT; furthermore, in vitro studies demonstrated SPINK1 interacted with EGFR to promote the abilities of proliferation, migration and invasion attenuated by SPINK1 si-RNA via ERK, p38, and JNK pathways. SPINK1 was also found to regulate radio-resistance in CRC cell lines. In conclusion, SPINK1 expression is an independent prognostic marker in patients receiving pre-operative CCRT, and SPINK1 regulates proliferation, migration and invasion via EGFR-downstream ERK, p38 and JNK pathways. The phenotypes of radiosensitivity that could be reversed with attenuation of SPINK1 levels suggest that targeting SPINK1 might offer a strategy for optimal precision medicine.
丝氨酸蛋白酶抑制剂 Kazal 型 1（SPINK1）是一种胰蛋白酶激酶抑制剂，已知与炎症和发病机制有关。本研究旨在证明 SPINK1 在接受同期放化疗（CCRT）的直肠癌（RC）患者中的临床病理作用和进展。对 111 例 RC 病例的 SPINK1 蛋白表达进行免疫组织化学染色显示，高 SPINK1 表达与神经周围侵犯和 CCRT 前标本反应不良显著相关。此外，多变量分析表明，在接受术前 CCRT 的 RC 患者中，CCRT 前 SPINK1 表达是总生存和无病生存的显著预后标志物；此外，体外研究表明，SPINK1 通过 ERK、p38 和 JNK 途径与 EGFR 相互作用，削弱了 SPINK1 si-RNA 的增殖、迁移和侵袭能力。还发现 SPINK1 调节 CRC 细胞系的放射抗性。总之，SPINK1 表达是接受术前 CCRT 的患者的独立预后标志物，SPINK1 通过 EGFR 下游的 ERK、p38 和 JNK 途径调节增殖、迁移和侵袭。SPINK1 水平降低可逆转的放射敏感性表型表明，针对 SPINK1 可能为最佳精准医学提供一种策略。
