Jiang Haizhong, Li Xueying, Zhou Feng, Xi Yang, Xu Guoqiang
Department of Gastroenterology, First Affiliated Hospital, School of Medicine, Zhejiang University, 310003, Hangzhou, China.
Department of Gastroenterology, First Affiliated Hospital, Ningbo University, Ningbo, Zhejiang, 315000, China.
Heliyon. 2024 May 20;10(11):e31431. doi: 10.1016/j.heliyon.2024.e31431. eCollection 2024 Jun 15.
Colorectal cancer is one of the most common malignancies and ranks second in terms of cancer-related mortality worldwide due to its metastasis, drug resistance, and reoccurrence. High-mobility gene group A2 (HMGA2) is overexpressed in colorectal cancer, contributing to the aggressiveness of tumor malignance, and promotes drug resistance in many types of cancer. However, the underlying molecular mechanism of HMGA2 is yet to be elucidated. In this study, we showed that HMGA2 is overexpressed in colorectal cancer tissue, and knockdown of HMGA2 significantly inhibited colorectal cancer cell growth and migratory capability. HMGA2 regulates the cancer cell response to a widely used anti-cancer drug, paclitaxel (PTX). HMGA2 knockdown increased cell death, whereas HMGA2 overexpression decreased cell death after PTX treatment. Furthermore, lower reactive oxygen species (ROS) levels and mitochondrial potential were detected in HMGA2 overexpression cells after PTX treatment. However, HMGA2 knockdown produced the opposite effect. RNA sequencing showed a p53 signaling pathway-dependent regulation in HMGA2 knockdown cells. Combined with p53 inhibitors and HMGA2 knockdown, a synergetic effect of more cell death was observed in colorectal cancer cells after PTX treatment. Thus, we showed that HMGA2 can activate p53 signaling to regulate colorectal cancer cell death after PTX treatment. Altogether, our results reveal novel insights into the molecular mechanisms underlying HMGA2-mediated cancer cell resistance against PTX and highlight the potential of targeting HMGA2 and p53 signaling for the therapeutic investigation of colorectal cancer.
结直肠癌是最常见的恶性肿瘤之一，由于其转移、耐药性和复发，在全球癌症相关死亡率中排名第二。高迁移率族蛋白A2（HMGA2）在结直肠癌中过度表达，导致肿瘤恶性程度增加，并在多种癌症中促进耐药性。然而，HMGA2的潜在分子机制尚待阐明。在本研究中，我们发现HMGA2在结直肠癌组织中过度表达，敲低HMGA2可显著抑制结直肠癌细胞的生长和迁移能力。HMGA2调节癌细胞对广泛使用的抗癌药物紫杉醇（PTX）的反应。敲低HMGA2可增加细胞死亡，而PTX处理后过表达HMGA2则可减少细胞死亡。此外，PTX处理后，HMGA2过表达细胞中的活性氧（ROS）水平和线粒体电位较低。然而，敲低HMGA2则产生相反的效果。RNA测序显示敲低HMGA2的细胞中存在p53信号通路依赖性调节。联合使用p53抑制剂和敲低HMGA2，PTX处理后的结直肠癌细胞中观察到更多细胞死亡的协同效应。因此，我们表明HMGA2可激活p53信号通路以调节PTX处理后的结直肠癌细胞死亡。总之，我们的结果揭示了HMGA2介导的癌细胞对PTX耐药的分子机制的新见解，并突出了靶向HMGA2和p53信号通路用于结直肠癌治疗研究的潜力。
