Identification of the Novel Tumor Suppressor Role of FOCAD/miR-491-5p to Inhibit Cancer Stemness, Drug Resistance and Metastasis via Regulating RABIF/MMP Signaling in Triple Negative Breast Cancer

Abstract

Triple negative breast cancer (TNBC) possesses poor prognosis mainly due to development of chemoresistance and lack of effective endocrine or targeted therapies. MiR-491-5p has been found to play a tumor suppressor role in many cancers including breast cancer. However, the precise role of miR-491-5p in TNBC has never been elucidated. In this study, we reported the novel tumor suppressor function of FOCAD/miR-491-5p in TNBC. High expression of miR-491-5p was found to be associated with better overall survival in breast cancer patients. We found that miR-491-5p could be an intronic microRNA processed form FOCAD gene. We are the first to demonstrate that both miR-491-5p and FOCAD function as tumor suppressors to inhibit cancer stemness, epithelial-mesenchymal transition, drug resistance, cell migration/invasion, and pulmonary metastasis etc. in TNBC. MiR-491-5p was first reported to directly target Rab interacting factor (RABIF) to downregulate RABIF-mediated TNBC cancer stemness, drug resistance, cell invasion, and pulmonary metastasis via matrix metalloproteinase (MMP) signaling. High expression of RABIF was found to be correlated with poor clinical outcomes of breast cancer and TNBC patients. Our data indicated that miR-491-5p and RABIF are potential prognostic biomarkers and targeting the novel FOCAD/miR-491-5p/RABIF/MMP signaling pathway could serve as a promising strategy in TNBC treatment.

Deoxythymidylate kinase (DTYMK) participates in cell cycle arrest to promote pancreatic adenocarcinoma progression regulated by miR-491-5p through TP53 and is associated with tumor immune infiltration

“…Targeting JMJD2B is one way that miR-491-5p has been shown to have an antitumor impact in ERα-breast cancer ( 35 ), while targeting this gene by frog oviduct protein hydrolyzate (ORPH) has been shown to increase metastasis in gastric cancer. HCC growth, metastasis, and glycolysis are all slowed by the miR-491-5p/PKM2 axis ( 36 ), and the discovery of the FOCAD/miR-491-5p axis has been shown to reduce cancer stemness, drug resistance, and the development of metastases ( 37 ). The interaction between linc01615 and miR-491-5p regulates the survival and metastasis of colorectal cancer cells ( 38 ).…”

Characterization of coagulation-related gene signature to predict prognosis and tumor immune microenvironment in skin cutaneous melanoma

“…DUSP6 is an oncogenic factor in melanoma, and DUSP4 can play its part in the survival and growth of melanoma cells by inhibiting the DUSP6 expression. Increased RABIF expression in breast and triple negative breast cancer patients is related to poorer outcome and considered a potential bioprognostic marker ( 37 ). MMP7 is a stromal lysin protein playing important roles in immunity, apoptosis, angiogenesis, and coagulation and is highly expressed in cancers of various types, including gastric cancer, uveal melanoma, and colon cancer, resulting in infiltration and metastasis of tumor cells ( 38 – 40 ).…”

“…One study revealed that increased C1QA expression was significantly related to a better prognosis in breast cancer ( 41 ). MiR-491-5p was reported to directly targeting RABIF to downregulate cell invasion, metastasis, and drug resistance in triple negative breast cancer ( 37 ).…”

Nanoparticle drug delivery systems responsive to tumor microenvironment: Promising alternatives in the treatment of triple‐negative breast cancer

“…Recent studies have demonstrated that the expression of enzymes associated with glycolysis in TNBC resistant TME also has obvious individual differences from other tumors, such as 6‐phosphogluconate dehydrogenase (Luo et al, 2022; Xu, Ren, & Cheng, 2023), enolase (Ma, Zhao, Zhang, et al, 2022). In addition, MMPs are also thought to be associated with TNBC resistance (Huang et al, 2021). Meanwhile, ABC transporter, mutations in DNA repair enzymes, drug targets mutation, and GSH S‐transferase which is considered to be another potential way to improve the drug resistance (Marra et al, 2020; Sharmin et al, 2021).…”