Wei Zhijiang, Liu Guiying, Jia Rufu, Zhang Wei, Li Li, Zhang Yuanyuan, Wang Zhijing, Bai Xiyong
The First Department of Tumor Surgery, Cangzhou Central Hospital, Cangzhou, 061001, Hebei, People's Republic of China.
The Brain Science Hospital of CangZhou Central Hospital, Cangzhou, 061001, Hebei, People's Republic of China.
Discov Oncol. 2023 Jan 3;14(1):1. doi: 10.1007/s12672-022-00535-9.
Aberrant expression of Secretory Leukocyte Protease Inhibitor (SLPI) has been associated with human cancer growth and its suppression was identified as a potential target for anti-cancer drugs, particularly in colorectal cancer. However, the underlying mechanism by which SLPI affected the development of drug resistance in CRC remains unclear.
This study investigated the role of SLPI in the p53-up-regulated modulator of apoptosis (PUMA)-mediated CRC cells' apoptosis and their chemosensitivity to Cisplatin.
A series of qRT-PCR and western blot analyses were performed to characterize the expressions of SLPI, PUMA, and Akt in CRC lines. Tunel, transwell, and CCK-8 analyses were monitored to define the impacts of the siRNA-mediated knockdown of SLPI on CRC cell development. Furthermore, in vivo development of CRC was evaluated in nude mice infected with siSLPI or Cisplatin alone or both, and Ki67 and caspase-3 immunohistochemistry assay was monitored on multiple tissue microarray from the same cohort.
Our results showed that SLPI inhibition strongly promoted the expressions of the pro-apoptotic protein PUMA, cleaved-caspase3 and Bax and reduced the cell viability of HT29 and HT116 cell lines in vitro. In addition, siSLPI knockdown effectively suppressed both Akt and FoxO3 proteins and improved the sensitivity to cisplatin chemotherapy. Xenograft tumor assay revealed a lowered growth in mice treated with Cisplatin, while combined treatment of siSLPI achieved more significant anticancer effects than Cisplatin alone.
Taken together, these findings demonstrated that suppression of SLPI might repress the growth of human colorectal cancer cells both in vitro and in vivo. These results suggested SLPI as a novel resistance factor to Cisplatin, and a combination of Cisplatin and SLPI inhibitor be beneficial for colorectal cancer therapy.
分泌型白细胞蛋白酶抑制剂（SLPI）的异常表达与人类癌症生长相关，其抑制作用被确定为抗癌药物的潜在靶点，尤其是在结直肠癌中。然而，SLPI影响结直肠癌耐药性发展的潜在机制仍不清楚。
本研究探讨SLPI在p53上调的凋亡调节因子（PUMA）介导的结直肠癌细胞凋亡及其对顺铂化疗敏感性中的作用。
进行一系列qRT-PCR和蛋白质印迹分析以表征SLPI、PUMA和Akt在结直肠癌细胞系中的表达。监测Tunel、transwell和CCK-8分析以确定siRNA介导的SLPI敲低对结直肠癌细胞发育的影响。此外，在单独感染siSLPI或顺铂或两者的裸鼠中评估结直肠癌的体内发育，并在来自同一队列的多个组织微阵列上监测Ki67和半胱天冬酶-3免疫组织化学分析。
我们的结果表明，SLPI抑制强烈促进促凋亡蛋白PUMA、裂解的半胱天冬酶3和Bax的表达，并降低HT29和HT116细胞系的体外细胞活力。此外，siSLPI敲低有效抑制Akt和FoxO3蛋白，并提高对顺铂化疗的敏感性。异种移植肿瘤试验显示顺铂治疗的小鼠生长降低，而siSLPI的联合治疗比单独使用顺铂具有更显著的抗癌作用。
综上所述，这些发现表明抑制SLPI可能在体外和体内抑制人结肠癌细胞的生长。这些结果表明SLPI是顺铂的一种新的耐药因子，顺铂和SLPI抑制剂联合使用对结直肠癌治疗有益。
