Synthetic miR-143 Inhibits Growth of HER2-Positive Gastric Cancer Cells by Suppressing KRAS Networks Including DDX6 RNA Helicase

Abstract

Gastric cancer (GC) is one of the most common cancers worldwide. In the clinical setting, the identification of HER2 overexpression in GC was a significant finding, as trastuzumab, an anti-HER2 drug, provides a survival advantage to HER2-positive GC patients. In HER2-postive GC, the dysregulation of PI3K/AKT and MAPK/ERK signaling pathways has been reported, and inhibition of these pathways is an important therapeutic strategy. MiR-143 is known to act as a tumor suppressor in several cancers, such as bladder cancer, breast cancer, colorectal cancer, and gastric cancer. In the current study, we developed a novel chemically-modified miR-143 and explored the functions of this synthetic miR-143 (syn-miR-143) in HER2-positive gastric cancer. The expression level of miR-143 was down-regulated in GC cell lines, including HER2-positive GC cell lines, MKN7, and KATO-III. The ectopic expression of miR-143 in those cell lines suppressed cell growth through systemic silencing of KRAS and its effector signaling molecules, AKT and ERK. Furthermore, syn-miR-143 indirectly down-regulated the expression of HER2, an upstream molecule of KRAS, through silencing DEAD/H-box RNA helicase 6 (DDX6), RNA helicase, which enhanced HER2 protein expression at the translational step in HER2-positive GC cells. These findings suggested that syn-miR-143 acted as a tumor suppressor through the impairment of KRAS networks including the DDX6.

High Expression of microRNA-143 is Associated with Favorable Tumor Immune Microenvironment and Better Survival in Estrogen Receptor Positive Breast Cancer

“…From the previous studies, miR-143 functioned as tumor suppressor miRNA in several malignancies through targeting KRAS and its effector molecules [10][11][12]. To explore the suppressive role of miR-143 associated with KRAS signaling pathways in breast cancer cells, we examined the expression levels of KRAS by western blot analysis and qRT-PCR.…”

“…Western blot analysis was performed as described in previous reports [10,11]. The following antibodies were used in this study.…”

“…OncomiRs mainly silence tumor suppressor genes and promote cancer progression, whereas tumor suppressor miRNAs mainly inhibit oncogenes and suppress cancer progression [5,6]. microRNA-143 (miR-143) is expressed in various malignancies, including breast, esophageal, gastric, and colorectal cancers, and has been reported to serve as a tumor suppressor miRNA [7][8][9][10][11]. Previous reports have revealed that miR-143 targets KRAS and its effector molecules to suppress the cell growth of gastric, colorectal and renal cell carcinomas [10][11][12].…”

“…microRNA-143 (miR-143) is expressed in various malignancies, including breast, esophageal, gastric, and colorectal cancers, and has been reported to serve as a tumor suppressor miRNA [7][8][9][10][11]. Previous reports have revealed that miR-143 targets KRAS and its effector molecules to suppress the cell growth of gastric, colorectal and renal cell carcinomas [10][11][12]. In breast cancer, miR-143 has been shown to suppress tumor growth, cell proliferation, cell invasion, and metastasis [13][14][15].…”

Effects of MIR143 on rat sarcoma signaling networks in solid tumors: A brief overview

“…Recently, we found that the expression level of MIR143‐3p is also downregulated in HER2‐positive GC cells and that ectopic expression of MIR143 induced cell growth suppression in those cells 52 . In that same study we demonstrated that MIR143‐3p targets KRAS effector signaling genes such as KRAS, AKT and ERK, leading to suppression of GC cell growth, and clarified that MIR143‐3p indirectly silences human epidermal growth factor receptor 2 (HER2), resulting in suppression of KRAS activation and its effector signaling pathways 52 …”