KIF20A/β-catenin轴调控宫颈癌顺铂耐药的机制研究

Chemo-resistance has been shown to be the main reason for the failure of cervical cancer treatment. Exploring molecular targets for enhancing chemo-sensitivity is the key to improve therapeutic effects. Our previous study has demonstrated that KIF20A is overexpressed in cervical cancer and upregulation of KIF20A is obviously correlated with tumor recurrence and poor prognosis. Further researches found that (a) KIF20A is upregulated in cervical cancer samples which are chemo-resistance. (b) overexpression of KIF20A enhanced cervical cancer stem cell characters and promoted the capacity of chemo-resistance to cisplatin; (c) co-immunoprecipitation assays showed that KIF20A interacted with β-catenin to regulate Wnt/β-catenin signaling pathway. Our findings suggested that KIF20A may play an important role in chemo-resistance of cervical cancer. However, the molecular mechanism via which KIF20A promotes the capacity of chemo-resistance via Wnt/β-catenin pathway is unknown. In our study, we aim to reveal the mechanism via which KIF20A activates Wnt/β-catenin pathway and consequently induces enhancement of cancer stem cell characters and cisplatin chemo-resistance from three levels of functional confirmation, mechanism analysis and clinical verification. Furthermore, the association between KIF20A/β-catenin and chemo-resistance would be evaluated in cervical cancer clinical specimens. Taken together, our findings will provide theoretical basis for potential therapeutic target of cervical cancer.

化疗耐药是造成宫颈癌患者治疗失败的主要原因，发掘化疗敏感性的分子靶标是提高疗效的关键。我们发现KIF20A在宫颈癌中呈高表达状态且与患者预后不良和肿瘤复发相关。进一步研究显示KIF20A在宫颈癌化疗耐药的临床样本中异常高表达；异常高表达的KIF20A可增强宫颈癌干细胞特征从而影响对化疗药物顺铂的耐药。免疫共沉淀实验表明KIF20A可与β-catenin直接结合调控Wnt信号通路的活化。前期结果提示：KIF20A在宫颈癌化疗耐药中发挥着重要作用，然而其激活Wnt/β-catenin信号通路调控化疗耐药的具体分子机制仍不清楚。本项目拟从功能确证-机制解析-临床验证三个层面，深入探讨KIF20A如何调控Wnt/β-catenin信号通路从而诱导宫颈癌干细胞特性增强及顺铂化疗耐药，并从大量临床样本中验证KIF20A/β-catenin对化疗耐药的影响，为寻找宫颈癌治疗新靶点奠定理论基础。

KIF20A在宫颈癌化疗耐药中发挥着重要作用，然而其激活Wnt/β-catenin信号通路调控化疗耐药的具体分子机制仍不清楚。本项目发现KIF20A在宫颈癌组织中表达上调，且与患者不良预后密切相关。KIF20A高表达增强宫颈癌细胞的肿瘤干细胞特性，促进肿瘤生长和顺铂的化疗抵抗。前期研究成果证实KIF20A可以与环状RNA circITGB6结合，然而其的生物学功能和分子机制仍不清楚，本项目发现肿瘤细胞与免疫微环境中的巨噬细胞通过细胞间分泌蛋白的作用，诱导肿瘤细胞铂类化疗耐药复发，并且提示靶向circITGB6可能成为逆转铂类化疗耐药的新型治疗手段。另外，本项目通过磁共振参数预测宫颈癌对化疗敏感性、淋巴血管间隙受累及肿瘤分化程度，阐明了在肿瘤进展过程中的影像学模型的新预测机制。我们的研究成果不仅为肿瘤的发生发展提供新的理论依据，并且项目研究中发现的多个重要基因可能成为临床肿瘤诊断、预后判断和治疗的潜在靶位点。因此，本项目的后续成果转化必将有助于解决宫颈癌的早诊率低、治疗手段有限、缺乏有效的检测与预防手段以及逆转宫颈癌的铂类化疗耐药，从而直接或间接地提高宫颈癌的治愈率和长期生存率，推进我国、我省和我市民生与社会发展中宫颈癌化疗耐药的研究及治疗重大科技问题的解决。