Adhesin Component Member STAG2 Enhances Cisplatin Tolerance in Colorectal Cancer Cells through the Epithelial-Mesenchymal Transition Pathway.

Pengjun Zhou, Meiyi Ye, Chunlan Chen, Rong Zhang
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Abstract

Background: Platinum-based compounds are commonly used as an initial treatment for colorectal cancer (CRC). However, the development of drug resistance in patients with CRC necessitates the administration of high drug concentrations during clinical treatment, thereby augmenting the toxicity of platinum-based compounds and increasing the mortality rate. STAG2 is a significantly associated drug-resistance gene in many cancers, but it has not been studied in colorectal cancer. Therefore, the present study aimed to investigate the role and drug sensitivity of the cisplatin-resistant gene STAG2.

Methods: The effects of STAG2 on drug resistance and survival rates of patients with CRC were examined using the Genomics of Drug Sensitivity in Cancer (GDSC) and Kaplan-Meier (KM) plotter databases. Subsequently, a sh-STAG2-HT-29 cell line was generated using a knockdown test of STAG2, and the half-maximal inhibitory concentration (IC50) of the two cell lines was determined using a cell viability test. We then used various techniques, including the Cell Counting Kit-8 (CCK-8), plate cloning, 5-ethynyl-2'-deoxyuridine (EdU) fluorescence staining, flow cytometry for cell cycle detection, the scar assay, the Transwell invasion assay, and Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) fluorescence staining for apoptosis detection, to investigate the functionality of the four subgroups of cancer cell lines. Additionally, Western blotting (WB) was used to identify the potential pathways associated with the observed functional alterations. Finally, the phenotype, tumor weight, mouse weight, tumor volume, and tumor tissue structure of the developed tumors were assessed using the subcutaneous tumor formation method.

Results: Database analysis indicated that STAG2 plays a role in facilitating drug resistance among individuals with CRC. Furthermore, mutations in this gene lead to increased sensitivity to cisplatin, and its overexpression was associated with an unfavorable prognosis. Following the successful development of STAG2 knockdown cells, differences in IC50 concentrations were observed between HT-29 and sh-STAG2-HT-29 cells. A treatment concentration of 10 μM cisplatin was selected, and the proliferation, migration, and invasion capabilities of cancer cells decreased after STAG2 knockdown. Additionally, the sensitivity of the cells to cisplatin therapy was increased, which was potentially mediated by the epithelial-mesenchymal transition (EMT) pathway. In mice, the tumorigenic potential of HT-29 cells was reduced by STAG2 knockdown, accompanied by a decrease in resistance to cisplatin therapy.

Conclusion: STAG2 acts as a proto-oncogene in CRC, and its resistance to cisplatin therapy is more prominent. This study confirmed the role of STAG2 in CRC and provided a theoretical basis for the further development of STAG2 as an auxiliary criterion for determining dosage when patients are treated with platinum drugs.

粘合素成分成员 STAG2 通过上皮-间质转化途径增强结直肠癌细胞的顺铂耐受性
背景:铂类化合物常用作结直肠癌(CRC)的初始治疗。然而,由于 CRC 患者耐药性的产生,在临床治疗过程中必须使用高浓度的药物,从而增加了铂类化合物的毒性并提高了死亡率。STAG2 在许多癌症中都是一个重要的相关耐药基因,但在结直肠癌中还没有相关研究。因此,本研究旨在探讨顺铂耐药基因 STAG2 的作用和药物敏感性:方法:利用癌症药物敏感性基因组学(GDSC)和 Kaplan-Meier (KM) plotter 数据库研究 STAG2 对 CRC 患者耐药性和生存率的影响。随后,我们利用 STAG2 基因敲除试验生成了 sh-STAG2-HT-29 细胞系,并利用细胞活力试验确定了两种细胞系的半数最大抑制浓度(IC50)。然后,我们采用了多种技术,包括细胞计数试剂盒-8(CCK-8)、平板克隆、5-乙炔基-2'-脱氧尿苷(EdU)荧光染色、用于检测细胞周期的流式细胞术、瘢痕测定、Transwell侵袭测定和用于检测细胞凋亡的Annexin V-异硫氰酸荧光素(FITC)/碘化丙啶(PI)荧光染色,来研究这四种亚组癌细胞株的功能。此外,还使用了 Western 印迹(WB)技术来确定与观察到的功能改变相关的潜在通路。最后,使用皮下肿瘤形成法评估了已形成肿瘤的表型、肿瘤重量、小鼠重量、肿瘤体积和肿瘤组织结构:结果:数据库分析表明,STAG2 在促进 CRC 患者产生耐药性方面发挥了作用。此外,该基因的突变会导致对顺铂的敏感性增加,其过表达与不良预后有关。在成功开发出 STAG2 敲除细胞后,观察到 HT-29 细胞和 sh-STAG2-HT-29 细胞的 IC50 浓度存在差异。选定的顺铂治疗浓度为 10 μM,STAG2 敲除后癌细胞的增殖、迁移和侵袭能力下降。此外,细胞对顺铂治疗的敏感性增加,这可能是由上皮-间质转化(EMT)途径介导的。在小鼠中,STAG2敲除可降低HT-29细胞的致瘤潜能,同时降低对顺铂治疗的耐药性:结论:STAG2 是 CRC 的原癌基因,其对顺铂治疗的耐药性更为突出。本研究证实了 STAG2 在 CRC 中的作用,并为进一步开发 STAG2 作为铂类药物治疗时确定剂量的辅助标准提供了理论依据。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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