磷酸酶PTP-PEST在多发性骨髓瘤发病中作用和机制研究

Multiple myeloma (MM) is a kind of hematological malignancy that causes great threat to life. However, the pathogenesis of MM remains unclear. PTP-PEST, as a new member of the protein tyrosine phosphatase family, is widely expressed in hematopoietic cells and regulates their differentiation, development and activation. In recent years, PTP-PEST is found to act as a tumor suppressor in many tumors, but the role of PTP-PEST in hematological malignancies, especially in the pathogenesis of MM is still obscure. Our preliminary results show that PTP-PEST expression is reduced in bone marrow samples from MM patients and a variety of MM cells lines. Overexpression of PTP-PEST could significantly inhibit the proliferation of MM cells, indicating PTP-PEST may be involved in the pathogenesis of MM. By overexpression or knock-down of PTP-PEST, the present study aims to explore the effect of PTP-PEST on the proliferation, apoptosis, cell cycle and drug sensitivity of MM cells, as well as their ability to form tumor in vitro. Our study will help to clarify the role and mechanism of PTP-PEST in MM pathogenesis, providing novel targets for the treatment and prognosis of MM.

多发性骨髓瘤（Multiple myeloma，MM）是严重威胁生命的血液系统恶性肿瘤，其发病机制仍不明确。PTP-PEST是酪氨酸磷酸酶家族的新成员，在造血细胞中广泛表达，可能与造血细胞的分化、发育、活化调控密切相关。近年来发现PTP-PEST能作为抑癌基因在许多肿瘤的发生、预后判断中发挥重要作用，但关于PTP-PEST在造血系统肿瘤尤其是MM发病中的作用尚不明确。本课题组的前期研究发现，PTP-PEST在MM患者骨髓标本和多种MM细胞株中表达明显降低，过表达PTP-PEST则能显著抑制MM细胞的增殖，进而提示PTP-PEST极有可能参与调控MM的发病。本研究拟通过过表达或干扰PTP-PEST，观察其对人MM细胞株增殖、凋亡、细胞周期、侵袭力、药物敏感性和体外成瘤能力的影响，以期初步阐明PTP-PEST在MM发病和耐药中的作用及机制，为临床上MM的治疗、预后判断提供新的干预靶点。

多发性骨髓瘤（Multiple myeloma, MM）是严重威胁生命的血液系统恶性肿瘤，其发病机制仍不明确。磷酸酶PTP-PEST是酪氨酸磷酸酶家族的新成员，在造血细胞中广泛表达，可能与造血细胞的分化、发育、活化调控密切相关。既往研究表明磷酸酶PTP-PEST能作为抑癌基因在许多实体肿瘤的发生、预后判断中发挥重要作用，但关于磷酸酶PTP-PEST在造血系统肿瘤尤其是MM发病中的作用尚不明确。本项目通过进一步研究，取得以下研究结果：磷酸酶PTP-PEST在MM细胞中的表达较正常浆细胞显著下降。随着MM病情的进展，PTP-PEST的表达呈下降趋势，并且其在复发MM病人中的表达较初治病人更低。在MM细胞株中过表达PTP-PEST能显著抑制MM细胞的增殖，而在MM细胞株中干扰PTP-PEST能显著促进MM细胞的增殖。过表达PTP-PEST后MM细胞阻滞于G0/G1期，细胞凋亡明显增加，细胞内caspase的活性明显增强。在MM耐药细胞株中过表达PTP-PEST能显著增强耐药细胞株对地塞米松、硼替佐米等化疗药物的敏感性。过表达PTP-PEST后MM细胞中NF-KB p65的磷酸化水平显著下降。体外成瘤试验表明，过表达PTP-PEST后MM细胞的体外成瘤能力显著弱于对照组细胞，表现为肿瘤生长明显减慢，体积明显减小，重量明显减轻。由此可见，磷酸酶PTP-PEST能作为抑癌分子抑制MM细胞的增殖、促进其凋亡，并且与其耐药性密切相关，有望成为MM治疗和预后评判的新靶点。