Theranostics 2018; 8(19):5452-5468. doi:10.7150/thno.28219

Research Paper

Adipocytes fuel gastric cancer omental metastasis via PITPNC1-mediated fatty acid metabolic reprogramming

Yujing Tan1*, Kelin Lin1*, Yang Zhao1*, Qijing Wu1, Dongping Chen2, Jin Wang3, Yanxiao Liang4, Jingyu Li5, Jiazhu Hu6, Hao Wang7, Yajing Liu1, Shuyi Zhang1, Wanming He1, Qiong Huang1, Xingbin Hu1, Zhiqi Yao1, Bishan Liang1, Wangjun Liao1, Min Shi1✉

1. Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
2. Department of Radiation Oncology, Affiliated Cancer Hospital & institute of Guangzhou Medical University, Guangzhou, China
3. Department of Abdominal Surgery, Affiliated Cancer Hospital & institute of Guangzhou Medical University, Guangzhou, China
4. Department of Pathology, Guangzhou First People's Hospital, Guangzhou, China
5. Department of Pathology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
6. Department of Oncology, Guangzhou Panyu Central Hospital, Guangzhou, China
7. Department of Pathology, Guangzhou Panyu Central Hospital, Guangzhou, China
*These authors contributed equally to this work.

Abstract

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.

Keywords: PITPNC1, gastric cancer, omental metastasis, fatty acid oxidation, anoikis resistance

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How to cite this article:
Tan Y, Lin K, Zhao Y, Wu Q, Chen D, Wang J, Liang Y, Li J, Hu J, Wang H, Liu Y, Zhang S, He W, Huang Q, Hu X, Yao Z, Liang B, Liao W, Shi M. Adipocytes fuel gastric cancer omental metastasis via PITPNC1-mediated fatty acid metabolic reprogramming. Theranostics 2018; 8(19):5452-5468. doi:10.7150/thno.28219. Available from http://www.thno.org/v08p5452.htm