骨桥蛋白剪接变异体通过肿瘤分泌环境的信号重塑影响结直肠癌化疗敏感性的机制研究

肿瘤化疗敏感性高度依赖于细胞环境分泌因子及相关信号的调节，与结直肠癌(CRC)的进展和预后密切相关。细胞因子样分泌型骨桥蛋白(OPN)影响肿瘤的化疗敏感性。我们证实，5-Fu处理的CRC细胞中出现3种OPN的剪接变异体，其中OPNc的增加最为显著；OPNc显著降低CRC的5-Fu敏感性；进而提出，5-Fu可触发CRC细胞内OPN的异常剪接，产生的OPNc作为肿瘤环境的应激信号源，诱导细胞耐药表型的出现，并通过效应的进行性放大和横向传播推动肿瘤耐药的进展。本项目拟明确OPN-SIs与CRC化疗失敏及不良预后的因果关系，揭示其应激信号传递及促发癌细胞化疗抵抗的生物学途径，解析细胞内OPN可变剪接分子调控机制。结果预期将确立OPNc是5-Fu化疗方案中具有重要临床参考意义的预后标志物；还将提示干预OPN的剪接产物生成以及阻断OPNc细胞应激信号通路可成为改善或逆转CRC化疗耐受的有效策略。

The chemosensitivity of tumor cells is highly influenced under regulation of microenvironmental secretory factors, which is also largely contributed to the progression and prognosis of colorectal cancer (CRC). Previous studies showed that osteopontin (OPN), as a cytokine-like secretory protein, was able to alter the chemosensitivity of tumor cells. We discovered that the expression of OPNc, one of 3 splicing isoforms of human OPN (OPNa, OPNb, OPNc) increased most significantly in colorectal cancer cells exposed to 5-fluorouracil (5-Fu), and OPNc in secretory forms significantly reduced the sensitivity of CRC cells to 5-Fu. We propose that 5-Fu triggers the abnormal splicing of OPN in CRC cells and the produced OPNc, functioned as a stress signal in the tumor microenvironment, could induce the emergence of drug resistant cell phenotype, thus to promote the progress of tumor chemoresistance through the process of effect amplification and horizontal transmission. The studies will validate OPNc to be used as a prognostic marker with important clinical significance in 5-Fu chemotherapies. The results will not only elucidate the generic regulatory mechanism of the production of splicing isoforms in CRC cells, but also will demonstrate that interfering the production of OPN-SIs or blocking the OPNc mediated stress signaling can be effective strategies to improve or recover the resistance of CRC chemotherapy.