Long non‑coding RNA GAS5 inhibits ovarian cancer cell proliferation via the control of microRNA‑21 and SPRY2 expression
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In recent decades, numerous long non‑coding (lnc)RNAs, including growth arrest‑specific transcript 5 (GAS5), have been demonstrated to exert promoting or suppressive effects in human cancers. Decreased expression of the lncRNA GAS5 was reported to promote cell proliferation, migration and invasion and indicate poor prognosis in ovarian cancer. However, the exact underlying molecular mechanism through which GAS5 is involved in ovarian cancer growth remains unknown. The present study aimed to investigate the regulatory mechanism of GAS5 in ovarian cancer cell proliferation. Quantitative polymerase chain reaction and western blot analysis were used to examine RNA and protein expression, respectively. An MTT assay was used to examine cell proliferation. A luciferase reporter gene assay was conducted to verify the targeting relationship. It was identified that the expression levels of GAS5 and Sprouty homolog 2 (SPRY2) were significantly downregulated, while the expression level of microRNA (miR)‑21 was significantly upregulated in ovarian cancer tissues and cell lines compared with adjacent non‑tumor tissues and normal ovarian epithelial cells, respectively. Downregulation of GAS5 was significantly associated with advanced clinical stage. Luciferase assay data indicated that miR‑21 was a direct target of GAS5 and that SPRY2 was a target gene of miR‑21 in ovarian cancer‑derived A2780 cells. GAS5 overexpression significantly inhibited the proliferation of ovarian cancer cells, which was accompanied by the downregulation of miR‑21 and the upregulation of SPRY2. The overexpression of miR‑21 caused a significant decrease in A2780 cell proliferation, which was accompanied by reduced SPRY2 expression. Furthermore, miR‑21 overexpression attenuated the suppressive effects of GAS5 on A2780 cell proliferation and rescued the promoting effects of GAS5 on SPRY2 expression. In addition, the knockdown of SPRY2 also rescued the suppressive effects of GAS5 on the proliferation of A2780 cells. In summary, our study demonstrates that GAS5 exerts a suppressive effect on the proliferation of ovarian cancer cells, at least in part via the inhibition of miR‑21 expression and subsequent increased SPRY2 expression. These findings suggest that the GAS5/miR‑21/SPRY2 signaling pathway may be a potential therapeutic target in ovarian cancer.Keywords:
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Abstract Long non-coding RNAs (lncRNAs) have emerged as important regulators of human cancers. LncRNA GAS5 (GAS5) is identified tumor suppressor involved in several cancers. However, the roles of GAS5 and the mechanisms responsible for its functions in gastric cancer (GC) have not been well undocumented. Herein, the decreased GAS5 and increased miRNA-106a-5p levels were observed in GC and cell lines. GAS5 expression level was significantly inversely correlated with miRNA-106a-5p level in GC tissues. Moreover, luciferase reporter and qRT-PCR assays showed that GAS5 bound to miRNA-106a-5p and negatively regulated its expression in GC cells. Functional experiments showed that GAS5 overexpression suppressed GC cell proliferation, migration, and invasion capabilities and promoted apoptosis, while miRNA-106a-5p overexpression inversed the functional effects induced by GAS5 overexpression. In vivo , GAS5 overexpression inhibited tumor growth by negatively regulating miRNA-106a-5p expression. Mechanistic investigations revealed that GAS5 overexpression inactivating the Akt/mToR pathway by suppressing miRNA-106a-5p expression in vitro and in vivo . Taken together, our findings conclude the GAS5 overexpression suppresses tumorigenesis and development of gastric cancer by sponging miR-106a-5p through the Akt/mToR pathway.
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Radiotherapy is an important therapeutic strategy for the treatment of numerous types of malignant tumors, including glioma. However, radioresistance and anti‑apoptotic mechanisms decrease the efficacy of radiotherapy in many patients with glioma. BMI1 polycomb ring finger oncogene (Bmi‑1) is an oncogene associated with radioresistance in tumor cells. MicroRNA (miRNA)‑128a is a brain-specific miRNA, which suppresses Bmi‑1 expression. The present study investigated the effects of various radiation intensities on U‑87 MG glioma cells, as well as the role of reactive oxygen species (ROS), Bmi‑1, and miRNA‑128a in the cellular response to radiotherapy. The response of U‑87 MG cells following exposure to X‑ray radiation was assessed using a cell growth curve and inhibition ratio. Cell cycle distribution and the levels of intracellular ROS were evaluated by flow cytometry. The mRNA expression levels of Bmi‑1 and those of miRNA‑128a in U‑87 MG cells exposed to X‑ray radiation were evaluated by reverse transcription‑quantitative polymerase chain reaction. X‑ray radiation did not decrease the number of U‑87 MG cells; however, it did inhibit cellular growth in a dose‑dependent manner. Following exposure to X‑ray radiation for 24 h, cell cycle distribution was altered, with an increase in the number of cells in G0/G1 phase. The mRNA expression levels of Bmi‑1 were downregulated in the 1 and 2 Gy groups, and upregulated in the 6 and 8 Gy groups. The expression levels of miRNA‑128a were upregulated in the 1 and 2 Gy groups, and downregulated in the 8 Gy group. The levels of ROS were increased following exposure to ≥2 Gy, and treatment with N-acetyl cysteine was able to induce radioresistance. These results suggested that U‑87 MG cells exhibited radioresistance. High doses of X‑ray radiation increased the expression levels of Bmi‑1, which may be associated with the evasion of cellular senescence. miRNA‑128a and its downstream target gene Bmi‑1 may have an important role in the radioresistance of U‑87 MG glioma cells. In addition, ROS may be involved in the mechanisms underlying the inhibitory effects of X‑ray radiation in U‑87 MG cells, and the downregulation of ROS may induce radioresistance.
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Long noncoding RNAs (lncRNAs) have emerged as important regulators of human cancers. LncRNA GAS5 (GAS5) is identified as a tumor suppressor involved in several cancers. However, the roles of GAS5 and the mechanisms responsible for its functions in gastric cancer (GC) have not been well documented. Herein, the decreased GAS5 and increased miRNA-106a-5p levels were observed in GC and cell lines. GAS5 level was significantly inversely correlated with miRNA-106a-5p level in GC tissues. Moreover, dual-luciferase reporter and qRT-PCR assays showed that GAS5 bound to miRNA-106a-5p and negatively regulated its expression in GC cells. Functional experiments showed that GAS5 overexpression suppressed GC cell proliferation, migration and invasion capabilities, and promoted apoptosis, while miRNA-106a-5p overexpression inverted the functional effects induced by GAS5 overexpression. In vivo, GAS5 overexpression inhibited tumor growth by negatively regulating miRNA-106a-5p expression. Mechanistic investigations revealed that GAS5 overexpression inactivated the Akt/mTOR pathway by suppressing miRNA-106a-5p expression in vitro and in vivo Taken together, our findings conclude the GAS5 overexpression suppresses tumorigenesis and development of gastric cancer by sponging miR-106a-5p through the Akt/mTOR pathway.
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Long noncoding RNAs (lncRNAs) have been identified to be critical functional regulator in the human tumors, while the deepgoing mechanism by which lncRNAs modulates the endometrial carcinoma is still elusive. In this work, we found that lncRNA GAS5 was under-expressed in the endometrial carcinoma tissue specimens, especially these samples with type 2 diabetes mellitus. Besides, the aberrant under-expression of GAS5 was correlated with the advanced tumor stage as well as poor prognosis outcome. In cellular experiments, GAS5 was decreased in the cells exposed to the high glucose. Enforced GAS5 expression repressed the tumor phenotype of endometrial carcinoma cells, including proliferation and invasion. Molecular mechanism study further demonstrated that GAS5 functioned as a sponge for miR-222-3p, abrogating its ability of inhibiting p27 protein expression. In conclusion, these results confirmed the vital regulation of GAS5/miR-222-3p/p27 axis in the endometrial carcinoma tumorigenesis.
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The recently discovered long noncoding RNAs have the potential to regulate many biological processes, which are aberrantly expressed in many tumor types. Our previous study showed that the long noncoding RNA-growth arrest-specific transcript 5 (GAS5) was decreased in lung cancer tissue, which contributed to the proliferation and apoptosis of nonsmall cell lung cancer (NSCLC). GAS5 was also associated with the prognosis of lung cancer patients. These results suggest that GAS5 may represent a novel prognostic indicator and a target for gene therapy in NSCLC. However, the expression and diagnosis significance of GAS5 in the plasma of NSCLC patients was unknown. The plasma samples were more readily available than the tissue samples in clinical, so we designed the study to investigate the diagnosis value of GAS5 in blood samples. In our study, 90 patients with NSCLC and 33 healthy controls were included. Blood samples were collected before surgery and therapy. We extracted the free RNA in the plasma and analyzed the expression of GAS5 with quantitative reverse transcription PCR. Suitable statistics methods were used to compare the plasma GAS5 levels of preoperative and postoperative plasma samples between the NSCLC patients and healthy controls. Receiver-operating characteristic curve analysis was used to evaluate the diagnostic sensitivity and specificity of plasma GAS5 in NSCLC. The results showed that GAS5 was detectable and stable in the plasma of NSCLC patients. Furthermore, the plasma levels of GAS5 were significantly down-regulated in NSCLC patients compared with healthy controls (P = 0.000). Moreover, GAS5 levels increased markedly on the seventh day after surgery compared with preoperative GAS5 levels in NSCLC patients (P = 0.003). GAS5 expression levels could be used to distinguish NSCLC patients from control patients with an area under the curve of 0.832 (P < 0.0001; sensitivity, 82.2%; specificity, 72.7%). The combination of the GAS5 and carcinoembryonic antigen could produce an area of 0.909 under the receiver-operating characteristic curve in distinguishing NSCLC patients from control subjects (95% confidence interval 0.857-0.962, P = 0.000). We have demonstrated that GAS5 expression was decreased in NSCLC Plasma. Plasma samples were more accessible than tissue samples in clinical; therefore, GAS5 could be an ideal biomarker for the diagnosis of NSCLC.
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B7 homolog 6 (B7‑H6) was recently discovered to act as a co‑stimulatory molecule. In particular, the expression of B7‑H6 has been found to play an important biological role in several types of tumors. The aim of the present study was to determine the role of B7‑H6 in cervical cancer. Immunohistochemistry was used to analyze the expression levels of B7‑H6 in cervical precancerous and cancerous tissues. Furthermore, the expression of B7‑H6 was knocked down in HeLa cells using short hairpin RNA and the effects of B7‑H6 on HeLa cell proliferation, migration and invasion were determined using Cell Counting Kit‑8, colony formation, wound healing and Transwell invasion assays, respectively. In addition, flow cytometry was used to analyze the levels of cell apoptosis and the cell cycle distribution. The results of the immunohistochemical staining revealed that the expression levels of B7‑H6 were upregulated in cervical lesions. Furthermore, the expression levels of B7‑H6 were positively associated with the clinical stage of the cervical lesions. B7‑H6 knockdown suppressed the invasive, migratory and proliferative abilities of HeLa cells, and promoted G1 cell cycle arrest and apoptosis. In conclusion, the findings of the present study suggested that B7‑H6 may serve as a novel oncogene and may hold promise as a potential therapeutic target for cervical cancer.
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Abstract Bipolar disorder (BD) patients suffer from severe disability and premature death because of failure in prognosis, diagnosis, and treatment. Although neural mechanisms of bipolar have not been fully discovered, studies have shown long noncoding RNAs (lncRNAs) can play an important role in signaling pathways such as PI3K/AKT pathway. There has been little study on deregulated lncRNAs and the lncRNAs’ mode of action in the BD. Hence, we aimed to investigate the expression of PI3K/AKT pathway-related lncRNAs named TUG1, GAS5, and FOXD3-AS1 lncRNAs in the PMBC in 50 bipolar patients and 50 healthy controls. Our results showed that FOXD3-AS1 and GAS5 under-expressed significantly in bipolar patients compared to healthy controls (P = 0.0028 and P < 0.0001 respectively). Moreover, after adjustment, all P values remained significant (q value < 0.0001). According to the ROC curve, AUC (area under the curve), specificity, and sensitivity of these lncRNAs, GAS5 and FOXD3-AS1 might work as BD candidate diagnostic biomarkers. Taken together, the current results highlight that the dysregulation of FOXD3-AS1 and GAS5 may be associated with an increased risk of BD.
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Emerging evidence suggests the critical function of microRNAs in regulating the growth of cancer cells. In the present study, it was demonstrated that miR‑221‑3p was overexpressed in non‑small cell lung cancer (NSCLC) tissues and cell lines compared with that noted in the normal controls. Downregulation of miR‑221‑3p suppressed the proliferation, colony formation and invasion of NSCLC cells. To further understand the molecular mechanisms underlying the potential oncogenic function of miR‑221‑3p in NSCLC, the downstream targets of miR‑221‑3p were predicted using bioinformatic databases. The prediction suggested the cell cycle regulator p27 as one of the targets of miR‑221‑3p. Molecular experiments showed that miR‑221‑3p was able to bind with the 3'‑untranslated region (UTR) of p27 and decreased the expression of p27 in NSCLC cells. Consistent with the suppressive role of p27 in controlling cell cycle progression, overexpression of miR‑221‑3p decreased the expression of p27 and promoted cell cycle progression from G1 to S phase. Collectively, our findings identified miR‑221‑3p as a novel regulator of NSCLC cell growth via modulating the expression of p27.
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Cervical cancer (CC) is the second most common cancer and the fourth leading cause of cancer-related death in women worldwide. Up to date, only a few of long noncoding RNAs (lncRNAs) have been functionally characterized. Here, we aimed to discover the functional roles of lncRNA GAS5-AS1. The GAS5-AS1 expression in CC tissues was markedly decreased when compared with that in the adjacent normal tissues. The downregulation of GAS5-AS1 was significantly correlated with the advanced FIGO stage, distant metastasis, lymphatic metastasis and poor prognosis in patients with CC. Functionally, GAS5-AS1 drastically reduced CC cell proliferation, migration and invasion in vitro, and remarkably suppressed CC tumorigenicity and metastasis in vivo. Mechanistically, it was found that GAS5-AS1 interacted with the tumor suppressor GAS5, and increased its stability by interacting with RNA demethylase ALKBH5 and decreasing GAS5 N6-methyladenosine (m6A) modification. Moreover, it was shown that m6A-mediated GAS5 RNA degradation relied on the m6A reader protein YTHDF2-dependent pathway. Our findings reveal an important mechanism of epigenetic alteration in CC carcinogenesis and metastasis.
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Early diagnosis of non-small cell lung cancer (NSCLC) is essential for patient treatment and prognosis. Long noncoding RNA (lncRNA) have potential roles in tumor initiation and differentiation. The objective of this study was to investigate whether the circulating lncRNA, growth arrest-specific transcript 5 (GAS5) and SOX2 overlapping transcript (SOX2OT), could be used as noninvasive biomarkers for NSCLC diagnosis. Moreover, we aimed at evaluating the association between lncRNA and the clinicopathological features of NSCLC in order to predict the cancer prognosis. The results showed significant downregulation of GAS5 expression and upregulation of SOX2OT in NSCLC patients compared with controls (P < 0.001). Furthermore, the expression level of GAS5 was declined in stage IV of NSCLC, but SOX2OT expression was increased sharply in stages III and IV. The expression levels of lncRNAs were used to distinguish NSCLC patients from control with an area under curve of 0.81 (sensitivity 82.5% and specificity 80%) for GAS5 and 0.73 (sensitivity 76.3% and specificity 78.6%) for SOX2OT. The combination of GAS5 and SOX2OT showed differentiation NSCLC patients from controls with increased sensitivity (83.8) and specificity (81.4). In conclusion, the newly developed diagnostic panel involving of circulating GAS5 and SOX2OT could be perfect biomarker for diagnosis and prognosis of NSCLC.
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