Osteosarcoma (OS) is one of the most frequent malignant bone tumor types. Traditional treatments of OS involve standard chemotherapy or combination with radiation before and after surgery. Cisplatin is one of the most effective chemotherapeutic drugs used for treating osteosarcoma. However, patients with advanced tumor stages develop cisplatin resistance, leading to a major clinical challenge. In this study, we investigated the roles of miR‐329‐3p in cisplatin sensitivity of osteosarcoma cells. We found miR‐329‐3p was significantly downregulated in osteosarcoma tissues compared with normal bone tissues. Overexpression of miR‐329‐3p suppressed osteosarcoma cell proliferation. Moreover, we observed low‐toxic cisplatin treatments suppressed miR‐329‐3p but higher concentrations of cisplatin‐induced miR‐329‐3p expression. In addition, miR‐329‐3p was significantly downregulated in cisplatin‐resistant Saos‐2 cells which displayed elevated glucose metabolism. Overexpression of miR‐329‐3p significantly impaired glucose metabolism of Saos‐2 cells. Bioinformatics analysis and luciferase assay consistently demonstrated the glycolysis enzyme, lactate dehydrogenase‐A (LDHA) was a direct target of miR‐329‐3p in osteosarcoma cells. Rescue experiments revealed restoration of LDHA in miR‐329‐3p‐overexpressed cisplatin‐resistant cells effectively recovered glucose metabolism, resulting in increased cisplatin resistance. This study demonstrates a miR‐329‐3p‐LDHA‐glucose metabolism‐cisplatin resistance axis in osteosarcoma cells, providing a miRNA‐based therapeutic strategy against chemoresistant osteosarcoma.

中文翻译：

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miR-329-3p的过表达通过靶向LDHA抑制葡萄糖代谢使骨肉瘤细胞对顺铂敏感

骨肉瘤（OS）是最常见的恶性骨肿瘤类型之一。OS 的传统治疗包括标准化疗或手术前后联合放疗。顺铂是治疗骨肉瘤最有效的化疗药物之一。然而，晚期肿瘤患者会产生顺铂耐药性，这导致了重大的临床挑战。在这项研究中，我们研究了 miR-329-3p 在骨肉瘤细胞顺铂敏感性中的作用。我们发现与正常骨组织相比，骨肉瘤组织中 miR-329-3p 显着下调。miR-329-3p的过表达抑制骨肉瘤细胞增殖。此外，我们观察到低毒顺铂治疗抑制了 miR-329-3p，但更高浓度的顺铂诱导的 miR-329-3p 表达。此外，miR-329-3p 在葡萄糖代谢升高的顺铂抗性 Saos-2 细胞中显着下调。miR-329-3p的过表达显着损害了Saos-2细胞的糖代谢。生物信息学分析和荧光素酶测定一致证明糖酵解酶乳酸脱氢酶-A（LDHA）是骨肉瘤细胞中miR-329-3p的直接靶标。救援实验表明，在 miR-329-3p 过表达的顺铂耐药细胞中恢复 LDHA 有效地恢复了葡萄糖代谢，导致顺铂耐药性增加。该研究证明了骨肉瘤细胞中的 miR-329-3p-LDHA-葡萄糖代谢-顺铂耐药轴，为化疗耐药性骨肉瘤提供了一种基于 miRNA 的治疗策略。