MiR-325 Promotes Oxaliplatin-Induced Cytotoxicity Against Colorectal Cancer Through the HSPA12B/PI3K/AKT/Bcl-2 Pathway
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ORIGINAL ARTICLE
MiR‑325 Promotes Oxaliplatin‑Induced Cytotoxicity Against Colorectal Cancer Through the HSPA12B/PI3K/AKT/Bcl‑2 Pathway Li Zhang1 · Heping Chen1 · Yueqiong Song1 · Qing Gu1 · Lu Zhang1 · Qin Xie1 · Jin Xu1 · Min Zhang1 Received: 10 April 2020 / Accepted: 21 August 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Background Oxaliplatin is one of the most effective chemotherapeutic drugs used for the treatment of colorectal cancer (CRC). However, intervention that attenuates the resistance of oxaliplatin is still required in the treatment of CRC. Aims To investigate the role of miR-325 in changing the oxaliplatin sensitivity to CRC cells. Methods Expression of miR-325 in colorectal cancer tissues and cell lines was measured by using qRT-PCR analysis. Cytotoxicity of oxaliplatin to control or miR-325-overexpressed HT29 and SW480 cells was evaluated by CCK-8 assays. Luciferase reporter assay was used to confirm the regulation of miR-325 on HSPA12B. Flow cytometry was performed to detect the mitochondrial membrane potential and cell apoptosis. Results Expression of miR-325 was decreased in colorectal cancer tissues and cell lines. However, overexpression of miR-325 can decrease the 50% inhibiting concentration of oxaliplatin to colorectal cancer cell lines HT29 and SW480. Mechanically, we confirmed that miR-325 targeted HSPA12B in colorectal cancer. Therefore, overexpression of miR-325 inhibited the phosphorylation of PI3K and AKT and decreased the expression of Bcl-2 to promote the oxaliplatin-induced mitochondrial apoptosis in colorectal cancer. Conclusions MiR-325 sensitizes the colorectal cancer cells to oxaliplatin-induced cytotoxicity through the HSPA12B/PI3K/ AKT/Bcl-2 pathway. Keywords Colorectal cancer · miR-325 · Oxaliplatin · HSPA12B · PI3K/AKT · Bcl-2
Introduction Colorectal cancer (CRC) is one of the most prevalent malignant tumors. As CRC has the characteristic of high metastasis, it ranks the fourth leading cause of cancer-related death. Despite advances of therapeutic strategies in recent decades, CRC remains a major health problem around the world [1–3]. For CRC patients, especially the patients at the advance stage of CRC, chemotherapy is a major approach to improve their 5-year survival rate. However, chemoresistance is still a major challenge, as most of the patients eventually experience tumor recurrence due to drug resistance [4, 5]. Mitochondria are the primary structures in controlling cell death [6]. The Bcl-2 family is classified into three * Min Zhang [email protected] 1
Department of Geriatrics, Sichuan Provincial People’s Hospital, 32# 2nd West Part of the 1st Ring Road, Chengdu 610072, China
groups which are as follows: antiapoptotic members, such as Bcl-2, Bcl-xL, and Mcl-1, and proapoptotic BH3 and proapoptotic Bak/Bax proteins [7]. Oxaliplatin, a third generation of platinum compound, is known to induce cross-linking of cancer cell DNAs and thus causes their apoptotic cell death [8–10]. Although oxaliplatin is the first pl
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