Research Paper Volume 14, Issue 9 pp 4137—4157

LncRNA CRART16/miR-122-5p/FOS axis promotes angiogenesis of gastric cancer by upregulating VEGFD expression

Junling Zhang1, *, , Xiaocong Pang2,3, *, , Lili Lei2,3, , Jixin Zhang4, , Xiaoqian Zhang5, , Ziyi Chen6, , Jing Zhu1, , Yong Jiang1, , Guowei Chen1, , Yingchao Wu1, , Tao Wu1, , Yisheng Pan1, , Yucun Liu1, , Yimin Cui2,3, , Xin Wang1, ,

  • 1 Department of General Surgery, Peking University First Hospital, Beijing 100034, China
  • 2 Institute of Clinical Pharmacology, Peking University, Beijing 100034, China
  • 3 Department of Pharmacy, Peking University First Hospital, Beijing 100034, China
  • 4 Department of Pathology, Peking University First Hospital, Beijing 100034, China
  • 5 Department of General Surgery, The Cancer Hospital of the Chinese Academy of Medical Sciences and China National Cancer Center, Beijing 100034, China
  • 6 Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
* Equal contribution

Received: November 10, 2021       Accepted: April 11, 2022       Published: May 10, 2022
How to Cite

Copyright: © 2022 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Background: We previously identified a novel lncRNA, CRART16, that could induce cetuximab resistance in colorectal cancer cells. This study explored the relationship of CRART16 expression to gastric cancer progression and the molecular mechanisms involved.

Methods: We evaluated CRART16 expression in gastric cancer tissues and adjacent normal tissues from the TCGA database and our hospital. Besides, we assessed its relationship with the overall survival (OS) of patients with gastric cancer. The effects of CRART16 on gastric cancer angiogenesis were determined by endothelial tube formation assay, spheroid sprouting assay, HUVEC invasion assay, and chick embryo chorioallantoic membrane (CAM) assay. The involvement of the lncRNA CRART16/miR-122-5p/FOS axis was analyzed by western blotting and dual-luciferase reporter assay. The functions of CRART16 were confirmed in xenograft mouse models.

Results: We found that CRART16 was substantially overexpressed in gastric cancer tissues compared with normal tissues, based on the TCGA database and our clinical samples. High expression of CRART16 correlated with more advanced tumor stages and poor prognosis. Overexpression of CRART16 in gastric cancer cells promoted proliferation, colony formation, angiogenesis, and bevacizumab resistance in vitro, and it promoted tumor growth and angiogenesis in vivo, and vice versa. CRART16 was found to downregulate miR-122-5p by acting as a sponge, upregulating the target oncogene FOS. Afterward, the increased FOS expression led to the upregulation of VEGFD.

Conclusion: Our findings demonstrate that CRART16 promotes angiogenesis in vitro and in vivo, and CRART16 is a prognostic marker and therapeutic target in gastric cancer.


3′-UTR: 3′ untranslated region; CAMs: chick chorioallantoic membranes; CCK-8: cell counting kit-8; VEGFD: vascular endothelial growth factor D; miRNA: microRNA; HER3: human epidermal growth factor receptor 3; HUVECs: human umbilical vein endothelial cells; PKUF: Peking University First Hospital; qRT-PCR: quantitative real-time polymerase chain reaction; STAD: stomach adenocarcinoma; TCGA: The Cancer Genome Atlas; CD31: platelet endothelial cell adhesion molecule-1 (PECAM-1, or CD31).