Aberrant Expression of miR-362 Promotes Lung Cancer Metastasis through Downregulation of Sema3A

Abstract

miR-362 is a recently discovered member of the microRNA family, and it modulates a variety of physical activities and plays an important role in the occurrence and development of many tumors. However, the biological functions of hsa-miR-362-5p in non-small-cell lung carcinoma (NSCLC) are unknown. Transwell assay and colony formation were used to determine the migration, invasion, and proliferation of NSCLC cells in vitro. A subcutaneous tumor model in nude mice was established to detect NSCLC tumor growth in vivo. The direct binding of miR-362 to the 3′UTR of Semaphorin 3A (Sema3A) was confirmed by luciferase reporter assay. In this study, we found that the level of miR-362 was higher in NSCLC tissues than in adjacent normal tissues and that the level of miR-362 expression was also elevated in five NSCLC cell lines (A549, 95-D, H1299, H292, and H460) relative to a human normal lung epithelial cell line (BEAS2B). Furthermore, miR-362 promoted NSCLC cell invasion, migration, and colony formation in vitro and tumor formation in vivo. Next, we identified the miR-362 target gene Sema3A, which is significantly correlated with metastasis. Sema3A expression was increased in normal tissues relative to NSCLC tissues. This result is consistent with the fact that miR-362 expression is negatively correlated with Sema3A expression in clinical tissue samples and indicated that miR-362 can regulate Sema3A expression in NSCLC cells and consequently affect NSCLC invasion, migration, and colony formation. Taken together, these findings on the newly identified miR-362/Sema3A axis elucidate the molecular mechanism of NSCLC invasion and migration and could lead to a potential therapeutic target in NSCLC treatment.

Overexpression of Semaphorin 3A Is a Marker Associated with Poor Prognosis in Patients with Nasopharyngeal Carcinoma

“…Some reports suggest that Sema3A acts as a tumor suppressor in certain cancers [30,31]. In contrast, other researchers have shown that Sema3A alters tumor cell behavior directly by influencing migration and growth, or indirectly by interfering with tumor angiogenesis and the immune response [1,24,32,33]. Our findings agree with the results derived from other solid tumors, including pancreatic, lung, and prostate cancers [20,21,23].…”

“…Moreover, Sema3A can affect cell phenotype indirectly by interfering with tumor angiogenesis and the immune response [12,13]. On the other hand, several reports suggest that Sema3A may be a potent tumor suppressor in oral and lung cancers [23,24]. Whether Sema3A functions as a tumor suppressor or tumor promoter is still unclear and may be cancer specific.…”

MiR-362-5p, Which Is Regulated by Long Non-Coding RNA MBNL1-AS1, Promotes the Cell Proliferation and Tumor Growth of Bladder Cancer by Targeting QKI

“…Studies found that miR-362-5p reduces the expression of tumor suppressor protein CYLD, which leads to activate the NF-kB pathway to promote the proliferation, migration, and invasion of hepatocellular carcinoma cells and human breast cancer cells (Ni et al, 2015;Ni et al, 2016). In addition, miR-362-5p directly binds and negatively regulates the expression of Semaphorin 3A (Sema3A) in non-small cell lung cancer (NSCLC) to enhance the cell invasion and migration in vitro and tumor formation in vivo (Luo et al, 2018). However, miR-362-5p also exhibits a tumor suppressive role in neuroblastoma by inhibiting cell proliferation and migration through PI3K-C2b (Wu et al, 2015).…”

“…The biological functions of miR-362-5p have been extensively reported in various types of cancers. Increasing numbers of studies indicate that miR-362-5p promotes cell proliferation, tumor growth, and metastasis in hepatocellular carcinoma, human breast cancer, and lung cancer (Ni et al, 2015;Ni et al, 2016;Luo et al, 2018). However, miR-362-5p inhibits proliferation and migration of neuroblastoma cells and it is downregulated in renal cell carcinoma (Wu et al, 2015;Ying et al, 2018).…”

Comparing MicroRNA Profilings of Purified HER-2-Negative and HER-2-Positive Cells Validates miR-362-5p/Sema3A as Characteristic Molecular Change in Triple-Negative Breast Cancers

“…Also, the negative correlation between miR-362 expression and Sema3A expression was observed in clinical NSCLC tissue samples. Aberration of the miR-362/Sema3A axis might be the molecular mechanism of NSCLC invasion and migration and could lead to a potential therapeutic target in NSCLC treatment [36]. Semaphorins are a large family including at least 30 members which are divided into 3 types: secretory, transmembrane, and GPI-anchored, and 8 subgroups.…”