This work aims to elucidate the effects and the potential underlying mechanisms of microRNA-216a-3p (miR-216a-3p) on the proliferation, migration, and invasion of gastric cancer (GC) cells. In this study, we revealed that the expression of miR-216a-3p was significantly elevated in GC tissues and cell lines. The different expression level of miR-216a-3p was firmly correlated with clinicopathological characteristics of GC patients. We next demonstrated that upregulation of miR-216a-3p could dramatically promote the ability of proliferation, migration, and invasion of GC cells using a series of experiments, whereas downregulation essentially inhibited these properties. Additionally, through bioinformatics analysis and biological approaches, we confirmed that runt-related transcription factor 1 (RUNX1) was a direct target of miR-216a-3p, and overexpression of RUNX1 could reverse the potential effect of miR-216a-3p on GC cells. Furthermore, mechanistic investigation using Western blot analysis showed that downregulation of RUNX1 by miR-216a-3p could stimulate the activation of NF-kappa B signaling pathway. In summary, this work proved that miR-216a-3p can promote GC cell proliferation, migration, and invasion via targeting RUNX1 and activating the NF-kappa B signaling pathway. Therefore, miR-216a-3p/RUNX1 could be a possible molecular target for innovative therapeutic agents against GC.
In this report, we aimed to explore the role and regulatory mechanism of microRNA-940 (miR-940) in bladder cancer development. The expressions of miR-940 in bladder cancer tissues and cells were measured. miR-940 mimics, miR-940 inhibitor small interference RNA against INPP4A (si-INPP4A), and GSK3 beta (si-GSK3 beta) and their corresponding controls were then transfected into cells. We investigated the effects of miR-940, INPP4A, or GSK3 beta on cell proliferation, migration, invasion, and apoptosis. Additionally, target prediction and luciferase reporter assays were performed to investigate the targets of miR-940. The regulatory relationship between miR-940 and the Wnt/beta-catenin pathway was also investigated. miR-940 was upregulated in bladder cancer tissues and cells. Overexpression of miR-940 significantly increased bladder cancer cell proliferation, promoted migration and invasion, and inhibited cell apoptosis. INPP4A and GSK3 beta were the direct targets of miR-940, and knockdown of INPP4A or GSK3 beta significantly increased cancer cell proliferation, migration, and invasion and inhibited cell apoptosis. After miR-940 overexpression, the protein expression levels of c-Myc, cyclin D1, and beta-catenin were significantly increased, and the expression levels of p27 and p-beta-catenin were markedly decreased. The opposite effects were obtained after suppression of miR-940. XAV939, a tankyrase 1 inhibitor that could inhibit Wnt/beta-catenin signaling, significantly reversed the effects of miR-940 overexpression on cell migration and invasion. Our results indicate that overexpression of miR-940 may promote bladder cancer cell proliferation, migration, and invasion and inhibit cell apoptosis via targeting INPP4A or GSK3 beta and activating the Wnt/beta-catenin pathway. Our findings imply the key roles of suppressing miRNA-940 in the therapy of bladder cancer.
Prostate cancer has become the most commonly diagnosed and the second leading cause of cancer-related deaths in males. The long noncoding RNA second chromosome locus associated with prostate-1 (SChLAP1) has been found to be overexpressed in a subset of prostate cancer. However, the significance and mechanism of SChLAP1 in prostate cancer are not well known. In this study, we explored the role of SChLAP1 in prostate cancer tissues, cell lines, and mouse models. The effect of SChLAP1 on miR-198 and MAPK1 was specifically examined. We found that SChLAP1 expression was significantly increased in prostate cancer cells and tissues. Knockdown of SChLAP1 promoted apoptosis and inhibited cell proliferation and invasion in vitro and in vivo. In addition, a potential bonding site between miR-198 and SChLAP1 was predicted, and a low expression of miR-198 was found in prostate cancer tissues and cells. Knockdown of SChLAP1 significantly increased the expression of miR-198, and SChLAP1 overexpression markedly decreased it, indicating that SChLAP1 acted as a negative regulator in the expression of miR-198. Furthermore, our results showed that SChLAP1 interacted with miR-198 and subsequently modulated the MAPK1 signaling pathway in prostate cancer. In conclusion, our study has identified a novel pathway through which SChLAP1 exerts its oncogenic role in prostate cancer at the level of miRNAs and provided a molecular basis for potential applications of SChLAP1 in the prognosis and treatment of prostate cancer.
Rap2B, belonging to the Ras superfamily, has been implicated in cancer development and functions as a tumor promoter. However, the role of Rap2B in cervical cancer is unknown. In this study, we investigated the expression pattern and biological functions of Rap2B in cervical cancer. The results showed that Rap2B was overexpressed in cervical cancer tissues and cell lines. Knockdown of Rap2B inhibited the proliferation, migration, and invasion of cervical cancer cells. In addition, our tumorigenesis assay showed that Rap2B knockdown suppressed cervical cancer cell growth and metastasis in vivo. We also found that the ERK1/2 signaling pathway is involved in the inhibitory effect of Rap2B knockdown on cervical cancer development. In conclusion, we suggest that Rap2B is an oncogene and may be a promising therapeutic target for cervical cancer.
This study aimed to investigate the clinical significance of cullin 3 expression in nasopharyngeal carcinoma (NPC), as well as to explore the regulatory mechanism of cullin 3 underlying the growth and metastasis of NPC cells. Our findings showed that the expression levels of cullin 3 were significantly increased in both NPC tissues and cell lines. A strong positive correlation was found between cullin 3 expression and the Ki-67-based proliferation index in NPC tissues. Moreover, cullin 3 overexpression was correlated with local relapse and distant metastasis in NPC patients. In vitro experiments showed that knockdown of cullin 3 caused a significant reduction in the proliferation of NPC cells, probably by inducing cell cycle arrest. In addition, downregulation of cullin 3 inhibited colony formation and the migratory and invasive capacities of NPC cells. The expression levels of PCNA and epithelial-to-mesenchymal transition (EMT)-related proteins were also meditated by cullin 3 in NPC cells. Based on these findings, we demonstrated that cullin 3 plays a promoting role in the malignant progression of NPC and suggest that the cullin 3-based ubiquitin proteasome pathway may be used as a promising therapeutic target for NPC.
Glioma is the most common and lethal malignant intracranial tumor. Long noncoding RNAs (lncRNAs) have been identified as pivotal regulators in the tumorigenesis of glioma. However, the role of lncRNA urothelial carcinoma-associated 1 (UCA1) in glioma genesis is still unknown. The purpose of this study was to investigate the underlying function of UCA1 on glioma genesis. The results demonstrated that UCA1 was upregulated in glioma tissue and indicated a poor prognosis. UCA1 knockdown induced by si-UCA1 significantly suppressed the proliferative, migrative, and invasive activities of glioma cell lines (U87 and U251). Bioinformatics analysis and luciferase reporter assay verified the complementary binding within UCA1 and miR-122 at the 3'-UTR. Functional experiments revealed that UCA1 acted as an miR-122 "sponge" to modulate glioma cell proliferation, migration, and invasion via downregulation of miR-122. Overall, the present study demonstrated that lncRNA UCA1 acts as an endogenous sponge of miR-122 to promote glioma cell proliferation, migration, and invasion, which provides a novel insight and therapeutic target in the tumorigenesis of glioma.
TMPRSS3 belongs to the large type II transmembrane serine protease (TTSP) family, which plays an important role in the development and progression of tumors. However, the function of TMPRSS3 in nasopharyngeal carcinoma (NPC) remains unclear. The present study aimed to examine the impact of TMPRSS3 on the proliferation, migration, and invasion of NPC cells and their potential mechanisms. Our results demonstrated that the expression of TMPRSS3 was obviously upregulated in human NPC tissues and cell lines. Knockdown of TMPRSS3 expression significantly suppressed the proliferation and tumorigenicity of NPC cells in vitro and in vivo. Furthermore, knockdown of TMPRSS3 inhibited migration and invasion, as well as prevented the EMT process in NPC cells. Finally, knockdown of TMPRSS3 attenuated activation of the PI3K/Akt signaling pathway in NPC cells. Taken together, the present study demonstrates that the knockdown of TMPRSS3 inhibits proliferation, migration, and invasion in human NPC cells through the inactivation of the PI3K/Akt signaling pathway. This study suggests that TMPRSS3 may be a potential therapeutic target for the treatment of NPC.
Gastric cancer (GC) is one of the most common cancers in the world. The cathepsin F (CTSF) gene has recently been found to participate in the progression of several types of cancer. However, the clinical characteristics and function of CTSF in GC as well as its molecular mechanisms are not clear. Six GC cell lines and 44 paired adjacent noncancerous and GC tissue samples were used to assess CTSF expression by quantitative polymerase chain reaction (qPCR). We used lentivirus-mediated small hairpin RNA (Lenti-shRNA) against CTSF to knock down the expression of CTSF in GC cells. Western blot and qPCR were used to analyze the mRNA and related protein expression. The biological phenotypes of gastric cells were examined by cell proliferation and apoptosis assays. Microarray-based mRNA expression profile screening was also performed to evaluate the potential molecular pathways in which CTSF may be involved. The CTSF mRNA level was associated with tumor differentiation, depth of tumor invasion, and lymph node metastasis. Downregulation of CTSF expression efficiently inhibited apoptosis and promoted the proliferation of GC cells. Moreover, a total of 1,117 upregulated mRNAs and 1,143 downregulated mRNAs were identified as differentially expressed genes (DEGs). Further analysis identified the involvement of these mRNAs in cancer-related pathways and various other biological processes. Nine DEGs in cancer-related pathways and three downstream genes in the apoptosis pathway were validated by Western blot, which was mainly in agreement with the microarray data. To our knowledge, this is the first report investigating the effect of CTSF on the growth and apoptosis in GC cells and its clinical significance. The CTSF gene may function as a tumor suppressor in GC and may be a potential therapeutic target in the treatment of GC.
Homeobox B5 (HOXB5), a member of the HOX gene family, has been shown to play an important role in tumor progression. However, the expression and functional role of HOXB5 in human non-small cell lung cancer (NSCLC) have not been defined. Thus, the purpose of this study was to elucidate the expression and functional role of HOXB5 in human NSCLC. Our results showed that HOXB5 expression was elevated in human NSCLC tissues and cell lines. The in vitro experiments demonstrated that knockdown of HOXB5 inhibited proliferation, migration, and invasion and prevented the EMT phenotype in NSCLC cells. In vivo experiments indicated that knockdown of HOXB5 attenuated the growth of NSCLC xenografts in vivo. Furthermore, knockdown of HOXB5 suppressed the protein expression levels of beta-catenin and its downstream targets c-Myc and cyclin D1 in A549 cells. Taken together, for the first time we have shown that knockdown of HOXB5 significantly inhibited NSCLC cell proliferation, invasion, metastasis, and EMT, partly through the Wnt/beta-catenin signaling pathway. These findings suggest that HOXB5 may be a novel therapeutic target for the treatment of NSCLC.
Colorectal carcinoma is one of the leading causes of cancer-related deaths and has a high tendency for metastasis, which makes it a priority to find novel methods to diagnose and treat colorectal carcinoma at a very early stage. We studied the role of the regulator of G-protein signaling (RGS) family of proteins RGS17 in colorectal carcinoma growth and metastasis. We found that RGS17 was upregulated in both clinical colorectal carcinoma tissues and cultured colorectal carcinoma cells. Knockdown of RGS17 by specific siRNA decreased the cell proliferation rate, whereas overexpression of RGS17 with expression plasmid increased the rate in cultured cells. Consistently, a mouse model for colorectal carcinoma also showed that depletion of RGS17 significantly inhibited tumor growth in vivo. Moreover, a Transwell assay showed that RGS17 promoted the ability of colorectal carcinoma cells to migrate and invade. These data suggest that RGS17 is overexpressed in colorectal carcinoma and promotes cell proliferation, migration, and invasion.
RBMS3, a gene encoding a glycine-rich RNA-binding protein, belongs to the family of c-Myc gene single-strand binding proteins (MSSP). Recently, several reports have provided evidence that RBMS3 was deregulated in a diverse range of solid tumors and played a critical role in tumor progression. However, it remains unclear whether RBMS3 inhibits the progression of human breast cancer. Thus, the aim of this study was to investigate the role of RBMS3 in breast cancer and explore the underlying mechanism in breast cancer progression. Our results showed, for the first time, that the expression of RBMS3 at both the mRNA and protein levels was significantly downregulated in human breast cancer tissues and cell lines. In addition, RBMS3 overexpression dramatically suppressed the proliferation, migration, and invasion of breast cancer cells in vitro and attenuated tumor growth in vivo. Furthermore, we observed that RBMS3 greatly inhibited the protein expression of beta-catenin, cyclin D1, and c-Myc in breast cancer cells. In summary, we have shown that RBMS3 inhibited the proliferation and tumorigenesis of breast cancer cells, at least in part, through inactivation of the Wnt/beta-catenin signaling pathway. Thus, RBMS3 may be a potential treatment target for breast cancer.
Epithelial-mesenchymal transition (EMT) is one of the most important mechanisms in the metastasis of various cancers, including gastric cancer (GC). In this study, we explored the putative significance of miR-644a and its role in EMT-mediated metastasis of GC. We first detected the expression of miR-644a in a cohort of 107 GC tissues using quantitative RT-PCR. The expression of miR-644a was suppressed in GC tissues and was associated with a later clinical stage and tumor metastasis. Restoring the expression of miR-644a could significantly suppress the migration and invasion of HGC-27 and SGC-7901 cells, which might be correlated to its suppressive effect on the EMT process. We also found that carboxyl-terminal-binding protein 1 (CtBP1) was a putative target gene of miR-644a in GC and might be involved in the suppressive effect. Collectively, through targeting CtBP1-mediated suppression of the EMT process, miR-644a might suppress the tumor metastasis of GC cells.
This study aimed to investigate the effect of dexmedetomidine (DEX) on osteosarcoma (OS) cell line MG63 and to explore the possible relationship between DEX and miR-520-3p in OS. The results showed that DEX could upregulate miR-520-3p, which directly targeted AKT1. Additionally, miR-520-3p also inhibited MG63 cell proliferation and migration, promoted apoptosis, and suppressed protein expressions of AKT, p-AKT, p-mTOR, and p-ER K1/2. DEX can inhibit OS cell proliferation and migration and promote apoptosis by upregulating the expression level of miR-520a-3p. DEX may serve as a potential therapeutic agent in OS treatment, and miR-520a-3p may be a potential target in the therapy of OS.
Oral submucous fibrosis (OSF) induced by chewing of the areca nut has been considered to be a precancerous lesion with a high probability of developing oral squamous cell carcinoma. Tanshinone (TSN) is the main component extracted from Salvia miltiorrhiza, a traditional Chinese medicine, which was found to have diverse pharmacological effects, such as anti-inflammatory and antitumor. In the current study, we aimed to identify the inhibitory effects and the underlying mechanism of TSN on OSF progress. We found that treatment with TSN inhibited the arecoline-mediated proliferation of primary human oral mucosal fibroblasts and reversed the promotive effects of arecoline on the EMT process. By RNA deep sequencing. we screened two possible targets for TSN: LSD1 and p53. We confirmed that p53 is much lower in OSF than in normal mucous tissues. In addition, p53 and its downstream molecules were decreased by arecoline treatment in oral mucosal fibroblasts. which was reversed by treatment with TSN in a dose-dependent manner. Our results also revealed that arecoline stimulation resulted in hypermethylation of the promoter of TP53 and subsequent downregulation of p53 levels, which was reversed by TSN. Furthermore, we identified that LSD1 could epigenetically activate TP53 by recruiting H3K27mel and H3K4m2 to its promoter. Our findings provide new insights into the mechanism by which TSN influences arecoline-induced OSF and rationale for the development of clinical intervention strategies for OSF and even oral squamous cell carcinoma.
The long noncoding RNA HOX transcript antisense RNA (HOTAIR) has been found to be overexpressed in many human malignancies and involved in tumor progression and metastasis. Although the downstream target through which HOTAIR modulates tumor metastasis is not well known, evidence suggests that microRNA-197 (miR-197) might be involved in this event. In the present study, the significance of HOTAIR and miR-197 in the progression of colorectal cancer was detected in vitro and in vivo. We found that HOTAIR expression was significantly increased in colorectal cancer cells and tissues. In contrast, the expression of miR-197 was obviously decreased. We further demonstrated that HOTAIR knockdown promoted apoptosis and inhibited cell proliferation, migration. and invasion in vitro and in vivo. Moreover, HOTAIR modulated the progression of colorectal cancer by competitively binding miR-197. Taken together, our study has identified a novel pathway through which HOTAIR exerts its oncogenic role and provided a molecular basis for potential applications of HOTAIR in the prognosis and treatment of colorectal cancer.