Role of hsa-miR-105 during the pathogenesis of paclitaxel resistance and its clinical implication in ovarian cancer
Role of hsa-miR-105 during the pathogenesis of paclitaxel resistance and its clinical implication in ovarian cancer
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DOI：
10.3892/or.2021.8035
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发表时间：
2021-05-01
期刊：
影响因子：
4.2
通讯作者：
An, Ruifang
中科院分区：
文献类型：
--
作者：
Li, Mao;Zhang, Shun;An, Ruifang
超过70%的上皮性卵巢癌（EOC）患者是全球妇科癌症相关死亡的主要原因之一，在疾病的晚期被诊断出来。目前，治疗晚期EOC的主要方法是肿瘤减瘤手术，然后联合铂和紫杉醇（PTX）为基础的化疗。然而，大多数患者最终会产生耐药性，这仍然是成功治疗的主要障碍。在此，通过使用临床标本和实验诱导的细胞模型，我们发现hsa-miR-105的表达水平在PTX耐药的EOC组织和细胞系中显著降低。后续功能实验表明，hsa-miR-105的抑制赋予了EOC细胞对紫杉醇的抗性，而通过瘤内注射hsa-miR-105 micrON（TM）阿戈米尔原位恢复hsa-miR-105表达增强了体内对PTX的敏感性，此后在PTX攻击的异种移植模型中显著抑制了肿瘤生长。hsa-miR-105通过直接抑制锌和环指2（ZNRF 2）信号通路发挥其肿瘤抑制功能。重要的是，肿瘤和循环样本中hsa-miR-105的异常表达预测了EOC患者化疗后的不良预后。这些发现共同表明，hsa-miR-105可能在EOC进展期间作为有效的肿瘤抑制miRNA，可能影响细胞增殖、侵袭性和对PTX的化学敏感性，并且至少部分地通过抑制ZNRF 2信号传导发挥作用。循环hsa-miR-105的稳定性和可用性以及易于测量使其成为EOC化疗的有价值的诊断/预后生物标志物候选物。
More than 70% of patients with epithelial ovarian cancer (EOC), one of the leading cause of gynecological cancer-related deaths worldwide, are diagnosed at an advanced stage of the disease. Currently, the mainstay for treatment of advanced EOC is tumor debulking surgery followed by combined platinum- and paclitaxel (PTX)-based chemotherapy. However, most patients eventually develop chemoresistance, which remains a major obstacle to successful treatment. Herein, by using clinical specimens and experimentally induced cell models, we found that the expression levels of hsa-miR-105 were significantly decreased in PTX-resistant EOC tissues and cell lines. Follow-up functional experiments demonstrated that repression of hsa-miR-105 conferred resistance to paclitaxel in EOC cells, whereas restoration of hsa-miR-105 expression in situ via intratumoral injection of hsa-miR-105 micrON (TM) agomir potentiated in vivo sensitivity to PTX and thereafter significantly inhibited tumor growth in a PTX-challenged xenograft model. Mechanistically, hsa-miR-105 exerted its tumor suppressor function by directly inhibiting the zinc and ring finger 2 (ZNRF2) signaling pathway. Importantly, aberrant expression of hsa-miR-105 in both tumor and circulating samples predicted a poor post-chemotherapy prognosis in EOC patients. These findings collectively suggest that hsa-miR-105 may act as a potent tumor suppressor miRNA during the progression of EOC, likely affecting cell proliferation, invasiveness and chemosensitivity to PTX, and functioning at least in part via inhibition of ZNRF2 signaling. The stability and availability and ease in measurement of circulating hsa-miR-105 make it a valuable diagnostic/prognostic biomarker candidate for chemotherapy of EOC.