Adipocytes fuel gastric cancer omental metastasis via PITPNC1-mediated fatty acid metabolic reprogramming
Adipocytes fuel gastric cancer omental metastasis via PITPNC1-mediated fatty acid metabolic reprogramming
复制标题
脂肪细胞通过PITPNC1介导的脂肪酸代谢重编程促进胃癌网膜转移
DOI：
10.7150/thno.28219
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发表时间：
2018-10
期刊：
影响因子：
12.4
通讯作者：
Shi Min
中科院分区：
文献类型：
--
作者：
Tan Yujing;Lin Kelin;Zhao Yang;Wu Qijing;Chen Dongping;Wang Jin;Liang Yanxiao;Li Jingyu;Hu Jiazhu;Wang Hao;Liu Yajing;Zhang Shuyi;He Wanming;Huang Qiong;Hu Xingbin;Yao Zhiqi;Liang Bishan;Liao Wangjun;Shi Min
大网膜转移在胃癌（GC）中经常发生，被认为是胃癌相关死亡的主要原因之一。最近的研究表明，网膜脂肪细胞可能介导这种转移倾向。磷脂酰肌醇转移蛋白胞质 1 (PITPNC1) 被确定在转移中具有至关重要的作用。然而，PITPNC1是否参与脂肪细胞与GC网膜转移之间的相互作用尚不清楚。方法：我们通过分析 TCGA 数据库以及使用匹配的 GC 组织、邻近正常胃粘膜组织（ANT）和大网膜转移组织进行免疫组织化学染色，对 PITPNC1 的表达进行了分析。通过共培养系统探索脂肪细胞对 PITPNC1 的调节。通过PITPNC1过表达和沉默两种方法，通过体外和体内实验确定了PITPNC1在失巢凋亡抵抗和转移中的作用。结果：PITPNC1在GC组织中的表达率高于ANT；值得注意的是，它在网膜转移性病变中更高。 PITPNC1 表达升高预示着网膜转移率较高和预后较差。 PITPNC1 通过上调 CD36 和 CPT1B 表达，通过脂肪酸代谢促进失巢凋亡抵抗。此外，PITPNC1 被脂肪细胞升高并促进 GC 网膜转移。最后，体内研究表明 PITPNC1 是脂肪酸氧化 (FAO) 抑制的治疗指标。结论： GC 中 PITPNC1 表达升高与临床分期晚期和预后不良相关。 PITPNC1通过增强FAO来促进失巢凋亡抵抗，FAO由大网膜脂肪细胞调节，从而促进GC大网膜转移。靶向 PITPNC1 可能是治疗网膜转移的一种有前景的策略。
Omental metastasis occurs frequently in gastric cancer (GC) and is considered one of the major causes of gastric cancer-related mortality. Recent research indicated that omental adipocytes might mediate this metastatic predilection. Phosphatidylinositol transfer protein, cytoplasmic 1 (PITPNC1) was identified to have a crucial role in metastasis. However, whether PITPNC1 participates in the interaction between adipocytes and GC omental metastasis is unclear. Methods: We profiled and analyzed the expression of PITPNC1 through analysis of the TCGA database as well as immunohistochemistry staining using matched GC tissues, adjacent normal gastric mucosa tissues (ANTs), and omental metastatic tissues. The regulation of PITPNC1 by adipocytes was explored by co-culture systems. By using both PITPNC1 overexpression and silencing methods, the role of PITPNC1 in anoikis resistance and metastasis was determined through in vitro and in vivo experiments. Results: PITPNC1 was expressed at higher rates in GC tissues than in ANTs; notably, it was higher in omental metastatic lesions. Elevated expression of PITPNC1 predicted higher rates of omental metastasis and a poor prognosis. PITPNC1 promoted anoikis resistance through fatty acid metabolism by upregulating CD36 and CPT1B expression. Further, PITPNC1 was elevated by adipocytes and facilitated GC omental metastasis. Lastly, in vivo studies showed that PITPNC1 was a therapeutic indicator of fatty acid oxidation (FAO) inhibition. Conclusion: Elevated expression of PITPNC1 in GC is correlated with an advanced clinical stage and a poor prognosis. PITPNC1 promotes anoikis resistance through enhanced FAO, which is regulated by omental adipocytes and consequently facilitates GC omental metastasis. Targeting PITPNC1 might present a promising strategy to treat omental metastasis.
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