Department of Otolaryngology Head and Neck, Nanjing Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, P.R. China.
Oncol Res. 2018 Dec 27;27(1):73-80. doi: 10.3727/096504018X15201099883047. Epub 2018 Mar 9.
Laryngeal carcinoma is a type of head and neck carcinoma with a high incidence and mortality. Chemotherapy treatments of human laryngeal carcinoma may fail due to the development of chemoresistance. Tissue inhibitor of metalloproteinase 3 (TIMP-3) has been shown to be implicated in a number of pathological processes typical for cancer. The present study aims to investigate the involvement of TIMP-3 in the chemoresistance of laryngeal carcinoma. We showed that TIMP-3 expression was significantly decreased in chemoresistant laryngeal carcinoma tissues compared with chemosensitivity tissues. Patients with low TIMP-3 expression exhibited poorer overall survival than those with high TIMP-3 expression. Moreover, cisplatin-resistant Hep-2 cells (Hep-2/R) were associated with the inhibition of mitochondrial membrane potential (MtMP) depolarization after cisplatin challenge. In addition, cisplatin resulted in a more pronounced mitochondrial cytochrome c release into the cytoplasm in Hep-2 cells than in their resistant variants. Overexpression of TIMP-3 by an adenovirus encoding TIMP-3 cDNA remarkably enhanced cisplatin-induced apoptosis, cytochrome c release, and caspase activation in Hep-2/R cells, thereby sensitizing cancer cells to cisplatin. On the other hand, downregulation of TIMP-3 markedly inhibited cisplatin-induced apoptosis in Hep-2 cells through attenuating mitochondria-dependent pathway activation. Taken together, these results demonstrate that decreased TIMP-3 expression may contribute to cisplatin resistance via inhibition of mitochondria-dependent apoptosis, indicating that forced TIMP-3 expression may be a useful strategy to improve the efficacy of cisplatin to treat laryngeal carcinoma.
喉癌是一种发病率和死亡率都很高的头颈部癌。人类喉癌的化疗治疗可能会因为产生化疗耐药性而失败。金属蛋白酶组织抑制剂 3（TIMP-3）已被证明与许多癌症特有的病理过程有关。本研究旨在探讨 TIMP-3 参与喉癌耐药性的机制。我们发现，与化疗敏感性组织相比，耐药性喉癌组织中 TIMP-3 的表达显著降低。TIMP-3 低表达的患者总生存率低于 TIMP-3 高表达的患者。此外，顺铂耐药的 Hep-2 细胞（Hep-2/R）在顺铂作用后表现出线粒体膜电位（MtMP）去极化的抑制。此外，与 Hep-2 细胞的耐药变体相比，顺铂导致更多的线粒体细胞色素 c 释放到细胞质中。通过腺病毒编码 TIMP-3 cDNA 的过表达，TIMP-3 显著增强了 Hep-2/R 细胞中顺铂诱导的细胞凋亡、细胞色素 c 释放和半胱天冬酶激活，从而使癌细胞对顺铂敏感。另一方面，下调 TIMP-3 通过抑制线粒体依赖性途径的激活，显著抑制了 Hep-2 细胞中顺铂诱导的细胞凋亡。综上所述，这些结果表明，TIMP-3 表达降低可能通过抑制线粒体依赖性凋亡导致顺铂耐药，表明强制 TIMP-3 表达可能是提高顺铂治疗喉癌疗效的一种有用策略。
