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Theranostics 2023; 13(14):5130-5150. doi:10.7150/thno.82492 This issue Cite

Research Paper

FN1 mRNA 3'-UTR supersedes traditional fibronectin 1 in facilitating the invasion and metastasis of gastric cancer through the FN1 3'-UTR-let-7i-5p-THBS1 axis

Siwei Pan^1,2#, Jiaming Zhu^1#, Pengfei Liu^1,2#, Qiaochu Wei^#1,2, Siyu Zhang³, Wen An¹, Yuxin Tong^3✉, Zhenguo Cheng^4✉, Funan Liu^1,2✉

1. Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education, Shenyang, 110016 China.
2. Phase I Clinical Trails Center, The First Hospital, China Medical University, 518 North Chuangxin Road, Baita Street, Hunnan District, Shenyang, 110102 Liaoning, China.
3. Medical Research Center, Liaoning Key Laboratory of Research and Application of Animal Models for Environmental and Metabolic Diseases, Shengjing Hospital of China Medical University, #36 Sanhao Street, Heping District, Shenyang 110004, China.
4. National Center for International Research in Cell and Gene Therapy, Sino-British Research Centre for Molecular Oncology, State Key Laboratory of Esophageal Cancer Prevention Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhenzhou 450000, China.
# Contributed equally.

✉ Corresponding authors: fnliuedu.cn (Funan Liu), czgtown_123com (Zhenguo Cheng), yxtongedu.cn (Yuxin Tong).

Abstract

Background: Current clinical treatments for gastric cancer (GC), particularly advanced GC, lack infallible therapeutic targets. The 3′-untranslated region (3′-UTR) has attracted increasing attention as a drug target.

Methods: In vitro and in vivo experiments were conducted to determine the function of FN1 3′-UTR and FN1 protein in invasion and metastasis. RNA pull-down assay and high-throughput sequencing were used to screen the factors regulated by FN1 3′-UTR and construct the regulatory network. Western blotting and polymerase chain reaction were used to examine the correlation of intermolecular expression levels. RNA-binding protein immunoprecipitation was used to verify the correlation between FN1 3′-UTR and target mRNAs.

Results: The FN1 3′-UTR may have stronger prognostic implications than the FN1 protein in GC patients. Upregulation of FN1 3′-UTR significantly promoted the invasive and metastatic abilities of GC cells to a greater extent than FN1 protein in vitro and in vivo. A novel regulatory network was constructed based on the FN1 3′-UTR-let-7i-5p-THBS1 axis, wherein FN1 3′-UTR displayed stronger oncogenic effects than the FN1 protein.

Conclusions: FN1 3′-UTR may be a better therapeutic target for constructing targeted drugs in GC than the FN1 protein.

Keywords: gastric cancer, FN1 3'-UTR, drug target, metastasis, small-molecule drugs

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