Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou 510080, China.
Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou 510080, China; The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510000, China.
Biochem Pharmacol. 2021 Jul;189:114390. doi: 10.1016/j.bcp.2020.114390. Epub 2020 Dec 22.
Matrix Gla protein (MGP), an extracellular matrix protein, has been widely reported to participate in the tumorigenic process and is abnormally expressed in several tumors. However, the role of MGP in colorectal cancer (CRC) remains unknown. Chemotherapy resistance represents a significant limitation in the treatment of CRC. Here, a comprehensive bioinformatics analysis revealed that MGP, which is overexpressed in CRC, might act as one of the critical genes conferring resistance to oxaliplatin (OXA). Furthermore, we found that MGP overexpression in tumor tissue might be correlated with cancer stage and patient prognosis, consistent with the bioinformatics analysis. The upregulation of MGP may act as an independent risk factor for CRC. The knockdown of MGP or inhibition of MGP expression significantly increased the sensitivity of the CRC cell lines to OXA. Suppression of MGP may reverse OXA resistance by upregulating copper transporter 1 (CTR1) and downregulating ATP7A and ATP7B. When used in combination with OXA, the inhibition of MGP reduced cancer cell proliferation, invasion, and migration and increased cell apoptosis in vitro. Suppression of MGP or OXA treatment alone significantly inhibited tumor growth in the CRC mouse model. Additionally, we found that OXA might promote the antitumor immune response in vivo. In summary, our study is the first to provide evidence that MGP expression confers OXA chemotherapy resistance in CRC and provides novel strategies to overcome chemotherapy resistance in CRC.
基质 Gla 蛋白（MGP）是一种细胞外基质蛋白，已广泛报道其参与肿瘤发生过程，并在几种肿瘤中异常表达。然而，MGP 在结直肠癌（CRC）中的作用尚不清楚。化疗耐药性是 CRC 治疗的一个重大限制。在这里，一项全面的生物信息学分析表明，CRC 中过表达的 MGP 可能是赋予奥沙利铂（OXA）耐药性的关键基因之一。此外，我们发现肿瘤组织中 MGP 的过表达可能与癌症分期和患者预后相关，与生物信息学分析一致。MGP 的上调可能是 CRC 的一个独立危险因素。MGP 的敲低或表达抑制显著增加了 CRC 细胞系对 OXA 的敏感性。抑制 MGP 可能通过上调铜转运蛋白 1（CTR1）和下调 ATP7A 和 ATP7B 来逆转 OXA 耐药性。当与 OXA 联合使用时，抑制 MGP 可减少体外癌细胞增殖、侵袭和迁移，并增加细胞凋亡。抑制 MGP 或单独使用 OXA 治疗可显著抑制 CRC 小鼠模型中的肿瘤生长。此外，我们发现 OXA 可能在体内促进抗肿瘤免疫反应。总之，我们的研究首次提供了证据表明 MGP 表达赋予 CRC 对 OXA 化疗的耐药性，并为克服 CRC 中的化疗耐药性提供了新策略。
