TGF-β1/DNMTs/CXCL12信号诱导胃癌细胞失巢凋亡抵抗和转移的作用机制

Anoikis resistance is key step in cancer cell metastasis. Recent studies have reported that down-expression of endogeneous CXCL12 modulates metastatic potential of many kinds of cancer. In our earlier study, DNA methylation plays the role in down-regulating endogeneous CXCL12 in gastric cancer cells. And the further study showed TGF-β1 up-regulates DNMT1 while down-regulating the CXCL12 expression. It was shown that TGF-β1 were critical in regulating anoikis resistance and metastasis in many kinds of tumor cells. It indicated that TGF-β1 was probably involved in the anoikis resistance and metastasis by regulating CXCL12 in gastric cancer cells. Accordingly, we put forward the hypothesis “TGF-β1 inducing CXCL12 down-expression with hypermethylated DNA in promoting anoikis resistance and metastasis of gastric cancer cells”. To confirm the hypothesis, we want to establish the relationship of TGF-β1, expression of CXCL12 and anoikis related index by genetic intervention and in vitro and in vivo experiments. And we clarified the mechanism of TGF-β1 in down-regulating CXCL12 in anoikis resistance and metastasis of gastric cancer cells to obtain new targets of intervention.

失巢凋亡抵抗是肿瘤转移重要环节。新近研究示多种肿瘤细胞内源性趋化因子CXCL12表达显著下降或缺失促进肿瘤侵袭转移。我们前期研究发现，启动子DNA甲基化可能导致人胃癌细胞中内源性CXCL12表达下调。进一步实验示TGF-β1上调DNMTs(甲基转移酶)抑制胃癌细胞内源性CXCL12表达。目前已知TGF-β1在调控多种肿瘤细胞失巢凋亡抵抗、促进转移中具有重要作用，提示TGF-β1可能调控内源性CXCL12表达参与胃癌失巢凋亡抵抗和促进转移。据此，我们提出“TGF-β1通过DNA甲基化诱导内源性CXCL12表达下调从而促进胃癌细胞发生失巢凋亡抵抗及侵袭转移”这一研究假设。为证实该假设，本课题拟通过基因干预和体内外实验等方法探讨TGF-β1调节内源性CXCL12表达下调的机制，阐明TGF-β1/DNMTs/CXCL12信号诱导胃癌细胞发生失巢凋亡抵抗及侵袭转移的作用机制，以期获得新的干预靶点。

胃癌仍是发展中国家高发肿瘤之一，在我国胃癌术后复发转移是胃癌致死的重要原因，肿瘤细胞发生失巢凋亡抵抗是肿瘤细胞转移的重要关键环节。本课题组前期研究表明, CXCL12在人胃癌细胞中表达下调。启动子DNA甲基化可能导致CXCL12表达下调。提出内源性CXCL12启动子DNA甲基化导致表达下调可能促进胃癌细胞侵袭转移。该项目证实CXCL12在人胃癌细胞中表达下调，且与胃癌患者生存期密切相关；内源性CXCL12启动子DNA甲基化导致表达下调可能促进胃癌细胞侵袭转移；TGF-β1通过DNA甲基化诱导内源性CXCL12表达下调从而促进胃癌细胞发生失巢凋亡抵抗及侵袭转移；TGF-β1通过上调DNMT1(甲基转移酶)抑制胃癌细胞内源性CXCL12表达。阐明在胃癌中TGF-β1/DNMTs/CXCL12信号诱导失巢凋亡抵抗及侵袭转移的机制，为胃癌防治提供新思路。