吉西他滨诱导胰腺星状细胞分泌CXCL14促进胰腺癌增殖转移的机制研究

Gemcitabine is the first-line chemotherapy drugs in pancreatic cancer, however, recovery or metastasis often occurs in the gaps between treatment cycles or after chemotherapy，and cause the failure of chemotherapy. Its mechanism is not clear at present. Our preliminary experiment displayed that，gemcitabine could promote proliferation and metastasis of pancreatic cancer cell line by stimulating pancreatic stellate cells (PSCs) to secrete CXCL14.CXCL14 could activate the β-catenin-EMT signaling pathways in pancreatic cancer cell lines. Therefore, we proposed a new hypothesis: gemcitabine induced PSC to secrete CXCL14, which promotes pancreatic cancer cells proliferation and metastasis, CXCL14-β-catenin-EMT signaling pathway is the main mechanism in the process. Hypotheses to be verified by the following researches: ①To determine the function of CXCL14 in the process of gemcitabine promote proliferation and metastasis of pancreatic cancer cell lines.②To confirm CXCL14 stimulates β-catenin-EMT signaling is the main mechanism in the process.③To investigate the potential diagnostic and prognostic significance of CXCL14 in pancreatic cancer. We expect to confirm and elucidate the exact role and mechanism of CXCL14-β-catenin-EMT signaling pathways in recovery or metastasis in the gaps between treatment cycles or after chemotherapy in pancreatic cancer.

吉西他滨是胰腺癌一线化疗药物，然而临床上吉西他滨化疗间隙或化疗后经常出现胰腺癌继续生长或远处转移，从而导致化疗失败，但其机制尚不清楚。前期我们发现，吉西他滨能够诱导胰腺星状细胞（PSCs）分泌CXCL14，同时CXCL14能够激活胰腺癌细胞株中β-catenin-EMT 信号通路。基于此我们提出假说：吉西他滨通过诱导PSCs分泌CXCL14促进胰腺癌细胞株增殖和转移，CXCL14-β-catenin-EMT信号通路是其主要作用机制。针对假说拟开展以下研究：①明确CXCL14在吉西他滨化疗间隙或化疗后促进胰腺癌细胞增殖和转移过程中的作用；②阐明CXCL14通过激活β-catenin-EMT信号促进胰腺癌增殖和转移的主要作用机制。③研究胰腺癌中CXCL14的表达对诊断和预后的意义。本研究将阐明CXCL14-β-catenin-EMT信号在胰腺癌吉西他滨化疗间隙或化疗后复发或转移中的作用及机制。

一线化疗药物吉西他滨对胰腺癌的临床疗效仍然不是十分理想。化疗间隙也让肿瘤细胞得以恢复,甚至获得更强的增殖、转移能力，发生肿瘤再次生长或者远处转移，从而导致化疗失败。胰腺星状细胞是胰腺癌基质的主要来源，对胰腺癌的生物学行为有着重要作用，然而在吉西他滨化疗间隙或化疗后，胰腺星状细胞会发生哪些变化，目前尚未见报道。本课题组主要探讨CXCL14对胰腺癌增殖及侵袭转移的影响及机制，以及CXCL14-β-catenin-EMT在吉西他滨化疗中的作用，和CXCL14在胰腺癌中的表达及意义。研究结果显示在吉西他滨化疗疗程间隙或结束后，胰腺星状细胞高分泌CXCL14，通过激活胰腺癌细胞中β-catenin-EMT信号，发挥促进胰腺癌增殖及转移的作用。本课题阐明了胰腺癌在吉西他滨化疗间隙或化疗后肿瘤再生增殖及转移的机制，并探讨CXCL14在判断胰腺癌预后及化疗反应中的价值，为开拓胰腺癌靶向治疗提供理论依据。