基于PKCα/JAK2/STAT3信号通路研究TM4SF1－DDR1复合体调控卵巢癌细胞侵袭转移相关机制

远处转移是影响卵巢癌预后的主要不良因素之一，但相关机制未完全明了。前期发现TM4SF1和DDR1在卵巢癌细胞膜上定位一致并相互作用，胶原蛋白Ⅰ可增强它们对侵袭转移的调控，均是治疗的靶点，但临床试验中单独抗TM4SF1、DDR1治疗效果不理想，提示其调控侵袭转移有更复杂机制。深入研究发现卵巢癌细胞存在有活性的PKCα/JAK2/STAT3通路，在胶原蛋白Ⅰ 刺激下同时下调TM4SF1+DDR1表达较分别下调单个基因更明显抑制PKCα、JAK2、STAT3的磷酸化程度。提出假说：TM4SF1与DDR1均为跨膜蛋白，在胶原蛋白Ⅰ的刺激下耦联为TM4SF1－DDR1复合体，继而激活PKCα/JAK2/STAT3通路调控卵巢癌细胞的侵袭转移，拟通过体外细胞及动物体内成瘤试验证实该假说。本研究有望阐明TM4SF1、DDR1联合调控侵袭转移的相关机制，为抗卵巢癌侵袭转移的靶向治疗提供新的靶点及理依据。

Distant metastasis is one of the main factors of poor prognosis in patients with ovarian cancer. The mechanism of cancer invasion and metastasis is not fully clear. Our study shew that：TM4SF1 and DDR1 had the same location on ovarian cancer cell membrane and interact with each other. TM4SF1 and DDR1 participated in the regulation of ovarian cancer cell invasion and metastasis. CollagenⅠenhanced the ability of their regulation invasion and metastasis. So TM4SF1 and DDR1 were potential targets for anti-tumor treatment. However, the targeted therapeutic effect of anti-TM4SF1 and anti- DDR1 alone in clinical trials was not ideal, which indicates that there are more complex mechanisms of TM4SF1 and DDR1 regulation invasion and metastasis. Further study indicated that there was an active PKCα/JAK2/STAT3 signaling pathway in ovarian cancer cells. Simultaneously RNAi the expression of TM4SF1 and DDR1 gene under the stimulation of Collagen I could more significantly inhibit the phosphorylation of PKCα, JAK2 and STAT3 than individually RNAi the expression of TM4SF1 or DDR1 gene. Hypothesis:TM4SF1 and DDR1, as transmembrane proteins, interact with each other, are coupled to form TM4SF1-DDR1 complex under the stimulation of CollagenⅠ. TM4SF1-DDR1 complex could activate the PKCα/JAK2/STAT3 signaling pathway to regulate the invasion and metastasis of ovarian cancer cells. This hypothesis is to be confirmed by in vitro cells experiments and animals into tumor experiments. This study is expected to clarify the relevant mechanism of TM4SF1 and DDR1 combined regulation of invasion and metastasis in ovarian cancer, and provide new targets and theoretical basis for targeted therapy against ovarian cancer invasion and metastasis.