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

被引:92
作者
Tan, Yujing [1 ]
Lin, Kelin [1 ]
Zhao, Yang [1 ]
Wu, Qijing [1 ]
Chen, Dongping [2 ]
Wang, Jin [3 ]
Liang, Yanxiao [4 ]
Li, Jingyu [5 ]
Hu, Jiazhu [6 ]
Wang, Hao [7 ]
Liu, Yajing [1 ]
Zhang, Shuyi [1 ]
He, Wanming [1 ]
Huang, Qiong [1 ]
Hu, Xingbin [1 ]
Yao, Zhiqi [1 ]
Liang, Bishan [1 ]
Liao, Wangjun [1 ]
Shi, Min [1 ]
机构
[1] Southern Med Univ, Nanfang Hosp, Dept Oncol, Guangzhou, Guangdong, Peoples R China
[2] Guangzhou Med Univ, Dept Radiat Oncol, Affiliated Canc Hosp & Inst, Guangzhou, Guangdong, Peoples R China
[3] Guangzhou Med Univ, Dept Abdominal Surg, Affiliated Canc Hosp & Inst, Guangzhou, Guangdong, Peoples R China
[4] Guangzhou First Peoples Hosp, Dept Pathol, Guangzhou, Guangdong, Peoples R China
[5] Southern Med Univ, Zhujiang Hosp, Dept Pathol, Guangzhou, Guangdong, Peoples R China
[6] Guangzhou Panyu Cent Hosp, Dept Oncol, Guangzhou, Guangdong, Peoples R China
[7] Guangzhou Panyu Cent Hosp, Dept Pathol, Guangzhou, Guangdong, Peoples R China
来源
THERANOSTICS | 2018年 / 8卷 / 19期
基金
中国国家自然科学基金; 中国博士后科学基金;
关键词
PITPNC1; gastric cancer; omental metastasis; fatty acid oxidation; anoikis resistance; OVARIAN-CANCER; PERITONEAL CARCINOMATOSIS; TUMOR DEPOSITS; CELL SURVIVAL; STRESS; PROGRESSION; ACTIVATION; PATHWAY; GROWTH; ENERGY;
D O I
10.7150/thno.28219
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 CPTIB 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 PITPNC 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.
引用
收藏
页码:5452 / 5468
页数:17
相关论文
共 40 条
[1]  
Bertero L, 2017, VIRCHOWS ARCH, P1
[2]   The role of the CCL22-CCR4 axis in the metastasis of gastric cancer cells into omental milky spots [J].
Cao, Liang ;
Hu, Xiang ;
Zhang, Jian ;
Huang, Gang ;
Zhang, Yi .
JOURNAL OF TRANSLATIONAL MEDICINE, 2014, 12 :1-10
[3]   A metabolic prosurvival role for PML in breast cancer [J].
Carracedo, Arkaitz ;
Weiss, Dror ;
Leliaert, Amy K. ;
Bhasin, Manoj ;
de Boer, Vincent C. J. ;
Laurent, Gaelle ;
Adams, Andrew C. ;
Sundvall, Maria ;
Song, Su Jung ;
Ito, Keisuke ;
Finley, Lydia S. ;
Egia, Ainara ;
Libermann, Towia ;
Gerhart-Hines, Zachary ;
Puigserver, Pere ;
Haigis, Marcia C. ;
Maratos-Flier, Elefteria ;
Richardson, Andrea L. ;
Schafer, Zachary T. ;
Pandolfi, Pier P. .
JOURNAL OF CLINICAL INVESTIGATION, 2012, 122 (09) :3088-3100
[4]   Peritoneal carcinomatosis [J].
Coccolini, Federico ;
Gheza, Federico ;
Lotti, Marco ;
Virzi, Salvatore ;
Iusco, Domenico ;
Ghermandi, Claudio ;
Melotti, Rita ;
Baiocchi, Gianluca ;
Giulini, Stefano Maria ;
Ansaloni, Luca ;
Catena, Fausto .
WORLD JOURNAL OF GASTROENTEROLOGY, 2013, 19 (41) :6979-6994
[5]  
Galluzzi L., 2018, CELL DEATH DIFFER, V1
[6]   Phosphatidylinositol Transfer Protein, Cytoplasmic 1 (PITPNC1) Binds and Transfers Phosphatidic Acid [J].
Garner, Kathryn ;
Hunt, Alan N. ;
Koster, Grielof ;
Somerharju, Pentti ;
Groves, Emily ;
Li, Michelle ;
Raghu, Padinjat ;
Holic, Roman ;
Cockcroft, Shamshad .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2012, 287 (38) :32263-32276
[7]   Microtargeting cancer metabolism: opening new therapeutic windows based on lipid metabolism [J].
Gomez de Cedron, Marta ;
Ramirez de Molina, Ana .
JOURNAL OF LIPID RESEARCH, 2016, 57 (02) :193-206
[8]   PITPNC1 Recruits RAB1B to the Golgi Network to Drive Malignant Secretion [J].
Halberg, Nils ;
Sengelaub, Caitlin A. ;
Navrazhina, Kristina ;
Molina, Henrik ;
Uryu, Kunihiro ;
Tavazoie, Sohail F. .
CANCER CELL, 2016, 29 (03) :339-353
[9]   Adipocytes promote malignant growth of breast tumours with monocarboxylate transporter 2 expression via β-hydroxybutyrate [J].
Huang, Chun-Kai ;
Chang, Po-Hao ;
Kuo, Wen-Hung ;
Chen, Chi-Long ;
Jeng, Yung-Ming ;
Chang, King-Jen ;
Shew, Jin-Yuh ;
Hu, Chun-Mei ;
Lee, Wen-Hwa .
NATURE COMMUNICATIONS, 2017, 8
[10]   Adipocyte p62/SQSTM1 Suppresses Tumorigenesis through Opposite Regulations of Metabolism in Adipose Tissue and Tumor [J].
Huang, Jianfeng ;
Duran, Angeles ;
Reina-Campos, Miguel ;
Valencia, Tania ;
Castilla, Elias A. ;
Mueller, Timo D. ;
Tschoep, Matthias H. ;
Moscat, Jorge ;
Diaz-Meco, Maria T. .
CANCER CELL, 2018, 33 (04) :770-+