蛋白络氨酸磷酸酶SHP2在子宫内膜癌中的作用及其分子机制研究

Endometrial cancer is one of the most common malignancies of female. Early stage endometrial cancer patients can be treated with progesterone therapy, surgery or chemo-radiotherapy. However, advanced stage patients or recurrent patients have no effective treatment. Our previous research revealed abnormal SHP2 expression was a uniform predictor of endometrial cancer and was correlated to EGFR expression. Suppression of SHP2 could inhibit endometrial cancer cell proliferation and promote apoptosis. The above findings indicated SHP2 may play an important role in endometrial cancer. Correlated references showed SHP2 could reverse EGFR inhibiter resistance by down-regulating ERK1/2 phosphorylation-level in lung cancer cells. So we assume that ‘ SHP2 can regulate EGFR/ERK signaling pathway to play an important role in endometrial cancer’. To verify this hypothesis, we will use cellular experiments to clarify the effect and mechanism of SHP2 influencing endometrial cancer cell biological behavior, progesterone therapy and targeted therapy, and further verify the results in vivo. Our research will provide new approaches for endometrial cancer treatment.

子宫内膜癌是女性常见恶性肿瘤，早期患者可进行孕激素治疗、手术治疗、放化疗等治疗，但晚期、复发患者尚无有效治疗手段。我们前期研究发现， SHP2在子宫内膜癌中异常表达，是评估子宫内膜癌预后的独立指标，并与EGFR表达相关。抑制表达SHP2可抑制子宫内膜癌增殖、加速凋亡，提示SHP2可能在子宫内膜癌中发挥重要作用。查阅相关文献发现，在肺癌细胞中抑制SHP2表达可降低ERK1/2磷酸化水平，逆转其对EGFR抑制剂的耐药。因此我们大胆推测“SHP2可通过调控EGFR/ERK信号通路在子宫内膜癌中发挥重要作用”。为验证这一假设，本课题拟通过细胞学实验明确SHP2对子宫内膜癌细胞生物学行为、孕激素治疗和靶向治疗的影响，阐明其具体分子机制，并通过动物体内实验进行验证。本课题的完成将为子宫内膜癌的治疗开辟新思路。

子宫内膜癌是女性常见恶性肿瘤，早期患者可进行孕激素治疗、手术治疗、放化疗等治疗，但晚期、复发患者尚无有效治疗手段。我们的研究发现，蛋白络氨酸磷酸酶SHP2在子宫内膜癌中异常表达，是评估子宫内膜癌预后的独立指标，与肿瘤的分级、肌层浸润以及淋巴结的转移密切相关。体外细胞功能学试验结果表明，SHP2过表达可抑制子宫内膜癌生殖、迁移，促进子宫内膜癌细胞凋亡，在子宫内膜癌的发生发展中，SHP2起抑癌基因的作用。在动物实验中，过表达SHP2 可明显抑制肿瘤生长、减少增殖相关蛋白Ki67的表达。进一步研究发现，SHP2可激活Erk通路，RNA-seq富集分析则提示其富集表达于与肿瘤相关通路。SHP2是子宫内膜癌靶向治疗的一个全新潜在靶点。