PDGFD的表观遗传学调控及其在肿瘤耐药中的作用

Platelet derived growth factor D (PDGFD) is found constitutively activated in many malignant tumors, and its over-expression is associated with tumor progression, relapse and poor prognosis. Activated PDGFD has been shown to play important roles in tumor proliferation, transformation, aggressiveness, angiogenesis and metastasis by activating downstream signaling pathways. Therefore, PDGFD can not only be used as an independent prognostic indicator in many cancers, it can also be treated as a potential target for targeted cancer therapy. In our previous studies, we found a distinct protein expression profile between pancreatic cancer cell line MiaPaca-2 and its gemcitabine-resistant cell line G3K, and PDGFD was found over-expressed in resistant cells. We found for the first time that the over-expression of PDGFD in resistant cells was the result of demethylation of PDGFD gene promoter. Moreover, PDGFD over-expression was first identified to contribute to gemcitabine resistance in pancreatic cancer cells with unknown mechanism. Therefore, by focusing on PDGFD, this study is designed to investigate its epigenetic regulation and the effect and underlying mechanisms of PDGFD mediated drug resistance. In addition, we are also intrigued to newly discover the relationship between PDGFD expression and prognosis of pancreatic cancer patients. Taken together, the outcome of this study will be of significant clinical values, and contribute to the grand goal of reversing the drug resistance of tumors.

PDGFD在多种恶性肿瘤中持续活化，其蛋白高表达与肿瘤的进展、复发和不良预后密切相关。活化的PDGFD通过激活下游信号通路促进肿瘤细胞增殖、转化、侵袭、血管生成和转移。因此，PDGFD不仅可作为独立的预后因素，也是一个潜在的抗肿瘤药物治疗靶点。在前期工作中，我们发现胰腺癌细胞系（MiaPaca-2）及其吉西他滨耐药株（G3K）具有迥异的蛋白表达谱，耐药株内PDGFD表达水平显著升高。我们首次发现在耐药细胞中，PDGFD的高表达是其基因启动子区发生去甲基化的结果，且高表达的PDGFD蛋白能够促进胰腺癌细胞对吉西他滨耐药。因此，本研究围绕PDGFD，探讨其具体的表观遗传学调控机制以及其介导的肿瘤细胞耐药机制，我们还将首次探索PDGFD表达与胰腺癌患者预后的相关性。本研究的最终成果将具有重大的临床指导意义，并为逆转肿瘤耐药这一宏伟目标添砖加瓦。

PDGFD在多种恶性肿瘤中持续活化，其蛋白高表达与肿瘤的进展、复发和不良预后密切相关。活化的PDGFD通过激活下游信号通路促进肿瘤细胞增殖、转化、侵袭、血管生成和转移。因此，PDGFD不仅可作为独立的预后因素，也是一个潜在的抗肿瘤药物治疗靶点。在前期工作中，我们发现胰腺癌细胞系（MiaPaca-2）及其吉西他滨耐药株（G3K）具有迥异的蛋白表达谱，耐药株内PDGFD表达水平显著升高。我们首次发现在耐药细胞中，PDGFD的高表达是其基因启动子区发生去甲基化的结果，且高表达的PDGFD蛋白能够促进胰腺癌细胞对吉西他滨耐药。因此，本研究主要探索表观遗传学改变与吉西他滨耐药的相关性，并围绕PDGFD，探讨其与获得性胰腺癌吉西他滨耐药的特异性以及PDGFD介导的肿瘤细胞耐药机制。本研究还通过小鼠体内实验验证PDGFD高表达对吉西他滨耐药的影响并探索胰腺癌患者组织中PDGFD的表达与患者预后的相关性，为胰腺癌的治疗提供潜在的分子靶点。