FABP4/EIF3/ATM/DNA损伤响应通路在脂肪细胞诱导胆管癌细胞放疗抵抗中的分子机制研究

Biliary tract cancers (BTCs) are a series of understudied and poorly understood collection of malignancies with a particularly poor prognosis. The radioresistance of BTC cells was thought to account for the unsatisfied effects of adjuvant radiotherapy. In our preliminary work, we for the first time showed that the omentum adipose could induce the radioresistance of BTC cell line RBE, which might be regulated by adipocytes-derived fatty acid binding protein 4 (FABP4), probably through EIF3/ATM/DNA damage response signaling. In the present study, we will extensively and exclusively investigate the mechanisms of FABP4 in mediating the adipocytes-induced radioresistance of BTC cells. The primary BTC cells and BTC cell lines with different FABP4 levels, along with the adipocytes with different FABP4 status will be used for adipocytes-BTC cells co-culture system. Corresponding assays and analysis will be performed to determine the regulatory roles of FABP4 in mediating adipocyte-induced radioresistance of BRC cells in vitro. Also, the correlation between the serum FABP4 level and the prognosis of BTC patients after radiotherapy will be preliminarily evaluated. The in vivo biological effects and mechanisms of FABP4 will be confirmed using patient derived tumor xenografts (PDTX) mice model. Further, the absolute quantification proteomics followed by signaling pathway methodology will be utilized, in order to verify the specific molecular mechanisms in context of FABP4/EIF3/ATM/DNA damage response signaling in mediating adipocytes-induced radioresistance of BTC cells. In summary, the present study will provide the basic laboratory evidences and preliminary clinical researches for BTCs, from a novel angel as the relationship between fatty acid metabolism / transportation and radiosensitivity regulation in BTCs.

胆管癌是预后极差的恶性肿瘤之一，胆管癌细胞对电离辐射的抗拒性是影响其放射治疗疗效的关键。课题组前期研究发现，肿瘤周围脂肪细胞可诱导胆管癌细胞的辐射抵抗；脂肪细胞来源的脂肪酸结合蛋白FABP4可能通过与真核细胞翻译起始因子3（EIF3）的相互作用，经ATM／DNA损伤响应通路参与脂肪细胞对胆管癌细胞放射敏感性的调控作用。本研究将采用脂肪细胞-胆管癌细胞共培养模型、人源胆管癌组织小鼠模型、以及相关临床样本，从整体水平、细胞水平、分子水平等不同层次，通过多种细胞生物学和分子生物学相关研究手段，进一步深入探讨FABP4/EIF3/ATM/DNA损伤响应通路在参与脂肪细胞对胆管癌细胞放射敏感性调控作用中的具体分子机制。预期本研究将从脂肪酸代谢与转运相关的新角度揭示胆管癌放射敏感性的调控机制，为胆管癌的临床治疗提供新的靶点理论研究依据。

胆管癌是预后极差的恶性肿瘤之一，胆管癌细胞对电离辐射的抗拒性是影响其放射治疗疗效的关键。本研究采用脂肪细胞-肿瘤细胞共培养模型和裸鼠移植瘤模型，不仅在胆管癌中，同时在胰腺癌和结直肠癌中明确了脂肪细胞可诱导肿瘤细胞的辐射抵抗。对相关调控分子机理进行研究发现，在胆管癌与胰腺癌中，脂肪细胞分泌的脂肪酸结合蛋白FABP4可与真核细胞翻译起始因子3（EIF3）相互作用，经ATM／DNA损伤响应通路介导脂肪细胞对肿瘤细胞放射敏感性的调控作用；此外发现，胆汁酸受体通路也参与了胆管癌辐射抵抗的调控机制；在结直肠癌中，脂肪细胞来源的外泌体，可通过外泌体包裹的微小RNA分子 miR-199-5p靶向JAG1，从而调控肿瘤细胞的放射敏感性。本研究所获相关结果，揭示了新的消化系统肿瘤放射敏感性的调控机制，为进一步挖掘具有转化价值的潜在新靶点提供了可靠的实验研究基础与理论依据。