High miR-200c expression is associated with suppressed epithelial-mesenchymal transition, TGF-β signaling and better survival despite enhanced cell proliferation in gastric cancer patients

Keiko Shichiri; Masanori Oshi; Danya Ziazadeh; Itaru Endo; Kazuaki Takabe

High miR-200c expression is associated with suppressed epithelial-mesenchymal transition, TGF-β signaling and better survival despite enhanced cell proliferation in gastric cancer patients

Am J Cancer Res. 2023 Jul 15;13(7):3027-3040. eCollection 2023.

Authors

Keiko Shichiri^{1

2}, Masanori Oshi^{1

3}, Danya Ziazadeh^{1

4}, Itaru Endo³, Kazuaki Takabe^{1

3

4

5

6

7}

Affiliations

¹ Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center Buffalo, NY 14263, USA.
² U.S. Naval Hospital Okinawa Okinawa, FPO, AP 96362, Japan.
³ Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine Yokohama, Kanagawa 236-0004, Japan.
⁴ Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York Buffalo, NY 14203, USA.
⁵ Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences Niigata 950-0883, Japan.
⁶ Department of Breast Surgery and Oncology, Tokyo Medical University Tokyo 160-8402, Japan.
⁷ Department of Breast Surgery, Fukushima Medical University Fukushima 960-8074, Japan.

PMID: 37560006
PMCID: PMC10408478

Abstract

MicroRNAs are small non-coding RNAs that epigenetically regulate gene expression. MiR-200c is a known tumor suppressive microRNA found in many types of cancer, and its high expression has been associated with improved prognosis. However, the association between miR-200c expression and its clinical relevance in gastric cancer (GC) patients remains controversial. Here, we hypothesized that gastric cancer patients with high miR-200c gene expression translated to better overall survival. A total of 372 GC patients from the Cancer Genome Atlas (TCGA) were analyzed. The top three quartiles were defined as a high miR-200c expression group. High miR-200c expression was associated with decreased invasion, favorable histological type, and improved overall survival in gastric cancer patients. Unexpectedly, high miR-200c expression GC was also associated with enhanced cell proliferation, shown by MKi67 expression, proliferation score, and enrichment of Hallmark cell proliferation-related gene sets (E2F targets, G2M checkpoints, MYC targets v1 and v2) by gene set enrichment assay (GSEA). High miR-200c GC was also associated with a high mutation rate and homologous recombination deficiency. Despite the association with elevated neoantigens, high miR-200c GC was associated with significantly low infiltration of anti-cancer immune cells, decreased immune response, and with suppressed IL2, TNF-α, and IFN-γ pathways. On the other hand, GC with low miR-200c expression significantly enriched hypoxia, angiogenesis, epithelial-mesenchymal transition (EMT), and TGF-β signaling gene sets, all of which promote cancer progression and metastasis in GSEA. In conclusion, patients with high miR-200c expression GC had better survival despite association with aggressive tumor biology, such as high mutation rates, cell proliferation, and low cancer immunity. Given that low miR-200c GC was associated with hypoxia, angiogenesis, EMT and TGF-β signaling, we cannot help but speculate that the difference in survival by miR-200c expression may be at least partly due to the association between low miR-200c expression and aggressive biology.

Keywords: EMT; Gastric cancer; angiogenesis; prognosis; signaling.