MicroRNA‑21 regulates the biological behavior of esophageal squamous cell carcinoma by targeting RASA1

Abstract

MicroRNA-21 (miR-21) has been revealed to play a crucial role in regulating the biological behavior, including proliferation, migration, invasion and metastasis in certain cancers. However, its role in esophageal squamous cell carcinoma (ESCC) has yet to be elucidated. Based on the data of GSE13937 downloaded from Gene Expression Omnibus (GEO) database, miR-21 was revealed to be one of the top 20 differentially expressed (DE) miRNAs screened using the Morpheus online tool. RAS p21 protein activator 1 (RASA1) was predicted as the target gene of miR-21 using the predicting software and was combined with miR-21 using the luciferase reporter assay. Its relative expression was significantly decreased, however, miR-21 was increased in the tumor tissues compared to the normal adjacent tissues in patients with ESCC as determined by quantitative polymerase chain reaction (q-PCR). Furthermore, overexpression of miR-21 (mimic) could significantly decrease the gene level of RASA1. Conversely, downregulation of miR-21 (inhibitor) significantly increased the gene level of RASA1, while downregulation of RASA1 (siRASA1) markedly increased the gene expression of miR-21. Notably, the expression of Snail and vimentin were significantly increased by upregulation of miR-21 and downregulation of RASA1. Transwell results revealed that miR-21 and RASA1 regulated proliferation, migration and invasion in ESCC cells. In an in vivo model, miR-21 inhibitor (antagomir) could inhibit tumor growth. In conclusion, miR-21 regulated cell proliferation, migration, invasion and tumor growth of ESCC by directly targeting RASA1, which may have been achieved via regulation of Snail and vimentin. Anti-miR-21 revealed an antitumor effect. Thus, it may be considered as a possible target for ESCC therapy.

Emerging Role of Non-Coding RNAs in Esophageal Squamous Cell Carcinoma

“…For example, miR-146a, miR-133b, miR-106b-3p, miR-219-5p, miR-206, miR-384, miR-455-5p, miR-128, miR-145-3p/5p, miR-10b-3p, miR-874-3p, miR-10a, miR-365, miR-301a, miR-6775-3p, miR-139-5p, miR-516b, miR-449a-5p, miR-125b, miR-433-3p, miR-370, miR-133b, miR-30a-3p/5p, miR-34a, miR-196a, and miR-125b-5p have been shown to act as tumor suppressors by inhibiting ESCC cell proliferation, promoting apoptosis by directly targeting oncogenes, or antagonizing pro-cancer signaling pathways [29,33,35,[40][41][42][43][44][45][46][47][48][49][50][51][52][54][55][56][57][58][60][61][62][63]110,133]. In contrast, pro-oncogenes such as miR-141, miR-21, miR-10b-3p, miR-424, miR-675-3p, miR-543, miR-135, miR-23b-3p, miR-502, miR-21-5p, and miR-548k have been reported to play contrasting roles in promoting cell proliferation or suppressing apoptosis in ESCC [47,[64][65][66][67][68][69][70][71][72][73]. Overall, the roles of miRNAs in cell proliferation and apoptosis can be crucial in ESCC pathogenesis.…”

Correlation of plasma miR-21 and miR-93 with radiotherapy and chemotherapy efficacy and prognosis in patients with esophageal squamous cell carcinoma

“…Previous studies have confirmed that miRNAs may become potential biomarkers for diagnosis, treatment, or prognosis of malignant tumors in clinical practice[9,10]. It has been proved that miR-21 is highly expressed in many solid tumors, such as ESCC, oral squamous cell carcinoma, and gastric cancer, so it is considered as a new target for cancer diagnosis or treatment[11]. Previous studies pointed out that miR-21 could regulate the invasion, migration, and epithelial-mesenchymal transition of esophageal carcinoma cells[12,13].…”

Cutting the Brakes on Ras—Cytoplasmic GAPs as Targets of Inactivation in Cancer

“…Intriguingly, miR-31 is a transcriptional target for mutated K-RAS in pancreatic tumors, where miR-31-mediated RASA1 inhibition creates a positive feedback that facilitates RhoA activation and cell migration and invasion [ 75 ]. Similarly, the miR-21/RASA1 axis was described in cervical cancer and esophageal squamous cell carcinoma, where miR-21 enhances Ras signaling and EMT [ 19 , 76 ]. High levels of miR-21 were found in the serum of cervical cancer patients, suggesting that secreted miR-21 can mediate RASA1 inhibition in a cell non-autonomous manner [ 76 ].…”

“…In early studies, RASA1 appeared to be essential for embryonic blood vessel development [ 13 ]; subsequently, a germline mutation in RASA1 was associated with vascular malformations [ 14 ]. Although RASA1 can mitigate Ras activity, its role in cancer has remained unclear for a long time; recent works described RASA1 inhibition by non-coding RNA in multiple aggressive tumors, supportive of a tumor-suppressive activity [ 15 , 16 , 17 , 18 , 19 ].…”