盐诱导激酶2在转移性卵巢癌脂代谢中的作用研究

In spite of high overall initial response to standard chemotherapy, the mortality rate of ovarian cancer patients remain high, which is mainly due to the progressive growth of recurrent chemotherapy-resistant disease and late presentation of metastatic disease in abdominal cavity. One of the main sites of ovarian cancer metastasis within the abdomen is the adipocyte-rich omentum. Previous studies have indicated that the adipocyte-rich microenvironment forms a niche for ovarian cancer metastasis, and that in metastatic omental lesions the activity of LKB1/AMPK/mTOR signaling is significantly up-regulated in adipocyte-cancer cell interface compared to other sites. We have shown that Salt-inducible Kinase 2 (SIK2), an AMPK-related protein kinase, is overexpressed in adipocyte-rich metastatic deposits compared to ovarian primary lesions. Importantly, the site where the highest SIK2 expression levels in the omentum were detected was at the interface between adipocytes and cancer metastasis. Adipocytes co-cultured with ovarian cancer cells significantly activated SIK2 and increased the proliferation and migration of the latter. Targeted depletion of SIK2 or its chemical inhibition prevented the adipocyte-mediated increase in cancer cell proliferation. Therefore we hypothesize that SIK2 activation is required for adipocyte-induced ovarian cancer cell proliferation and thus play an important role in the omental metastasis of ovarian cancer cells. A combination of direct analysis of histopathological samples, adipocyte-cancer cell co-culture, chemical biology and protein biochemistry will be incorporated to investigate the function and underlying mechanisms of SIK2-mediated adipocyte-rich metastasis of ovarian cancer, and thus shed light on targeting SIK2 as a potential therapeutic opportunity for this devastating disease.

卵巢癌广泛盆腹腔转移致肿瘤耐药是其致死的主要原因。临床发现卵巢癌易在网膜等脂肪丰富的组织和器官上种植转移。研究发现，脂肪细胞是卵巢癌转移至网膜的主要介质；腹腔大网膜转移的卵巢癌病灶中，紧邻脂肪组织的癌组织LKB1/AMPK/mTOR信号明显活跃于远离脂肪组织的癌组织。我们的研究发现AMPK蛋白家族之一盐诱导激酶SIK2在脂肪丰富组织的卵巢癌转移灶中的表达高于原发灶，在紧邻脂肪组织的癌组织的表达高于与远离脂肪组织的癌组织；脂肪细胞与卵巢癌细胞共培养使其增殖能力增强，但当抑制卵巢癌细胞中SIK2的表达后，脂肪细胞的促进增殖作用消失。因此我们设想SIK2蛋白通过介导脂肪细胞与肿瘤细胞间作用，进而调控肿瘤细胞脂代谢和增殖，从而在卵巢癌细胞腹腔网膜转移中起着重要的作用。我们拟借助分子生物学技术，结合组织病理学及细胞培养方法，揭示SIK2在卵巢癌腹腔转移机制中的作用，为卵巢肿瘤的分子治疗找到新的靶点。

临床工作中发现卵巢癌易于向富脂组织转移，然而其具体机制尚不十分清楚。本研究旨在阐明卵巢癌脂质代谢活性在肿瘤恶性进展中的作用，故而，我们利用卵巢癌组织、细胞系以及动物实验，从三个层面证实了SIK2在卵巢癌中表达上调，通过激活PI3K/AKT信号通路，提高SREBP1c及SREBP2表达水平，分别上调FASN及HMGCR，增加癌细胞内脂肪酸及胆固醇含量，促进卵巢癌细胞生长，为卵巢癌的临床治疗提供了一个新视角，是卵巢癌治疗的潜在靶点。