Knockdown of circMFN2 inhibits cell progression and glycolysis by miR-198/CUL4B pathway in ovarian cancer.

Circular RNA (circRNA) regulates malignant tumors, including ovarian cancer (OC). The present research study aimed to reveal the biological mechanism of circRNA mitofusin 2 (circMFN2) in OC. Cell biological behaviors were investigated using clonogenicity assay, EdU assay, transwell assay, and flow cytometry analysis. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot analysis were implemented to detect the levels of circMFN2, miR-198, Cullin 4B (CUL4B), and apoptosis-related proteins. Glycolysis was assessed by glucose assay kit, lactate assay kit, and ATP level detection kit. The relationships among miR-198, circMFN2, and CUL4B were verified by dual-luciferase reporter assay and RNA immunoprecipitation assay. The xenograft mice model was used to analyze tumor growth in vivo. The expression of circMFN2 and CUL4B was increased, while miR-330-5p was decreased in OC tissues or cells. The absence of CircMFN2 hindered cell proliferation, migration, invasion, and glycolysis and promoted apoptosis in OC cells. We found that circMFN2 promoted CUL4B expression via sponging miR-198. MiR-198 depletion reversed circMFN2 knockdown-induced effects in OC cells. Furthermore, CUL4B overexpression overturned the inhibitory effect of miR-198 in OC cells. And the absence of circMFN2 inhibited tumor growth in vivo. CircMFN2 repressed OC progression by regulating the miR-198/CUL4B axis.

circ_0002060 Enhances Doxorubicin Resistance in Osteosarcoma by Regulating the miR-198/ABCB1 Axis.

Background: Osteosarcoma (OS) is a common, aggressive primary sarcoma of bone. Drug resistance is a huge obstacle to chemotherapy for cancer. This study aimed to investigate the role and mechanism of circ_0002060 in OS resistance to doxorubicin (DOX). Methods: The levels of circ_0002060, miR-198, and ATP-binding cassette subfamily B member 1 (ABCB1) in OS tissues and DOX-resistant OS cells were measured by quantitative real-time polymerase chain reaction or Western blot assay. Kaplan-Meier analysis was performed to determine the relationship between circ_0002060 expression in OS tissues and overall survival of OS patients. The half-inhibitory concentration (IC50) of DOX was calculated using the Cell Counting Kit-8 (CCK-8) assay. Proliferation and apoptosis of DOX-resistant OS cells were assessed by colony formation assay and flow cytometry. The levels of apoptosis-related proteins in DOX-resistant OS cells were measured by Western blot assay. Xenograft assay was utilized to analyze the effect of circ_0002060 on DOX resistance in vivo. The interactions among circ_0002060, miR-198, and ABCB1 in DOX-resistant OS cells were confirmed by dual-luciferase reporter assay, RNA immunoprecipitation assay, or RNA pull-down assay. Results: circ_0002060 and ABCB1 were upregulated, while miR-198 was downregulated in OS tissues and DOX-resistant OS cells. circ_0002060 silencing reduced DOX resistance in vitro and in vivo. Moreover, circ_0002060 enhanced DOX resistance by sponging miR-198. Besides, miR-198 decreased DOX resistance by binding to ABCB1. In addition, circ_0002060 sponged miR-198 to upregulate ABCB1 expression. Conclusions: circ_0002060 promoted DOX resistance and OS progression by regulating the miR-198/ABCB1 axis, suggesting that circ_0002060 might be a promising biomarker for OS therapy.

Silencing of circ-CDK14 suppresses osteosarcoma progression through the miR-198/E2F2 axis.

BACKGROUND: Osteosarcoma (OS) is the most common primary bone malignancy. Circular RNAs (circRNAs) have been implicated in OS pathogenesis. In the current study, we explored the precise role of circRNA cyclin dependent kinase 14 (circ-CDK14, hsa_circ_0001721) in OS progression. METHODS: The levels of circ-CDK14, miR-198 and E2F transcription factor 2 (E2F2) were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Cell viability, apoptosis, migration and invasion were determined using the Cell Counting-8 Kit (CCK-8), flow cytometry and transwell assays, respectively. Glucose consumption, lactate production and adenosine triphosphate (ATP) level were gauged using the commercial assay kits. The direct relationship between miR-198 and circ-CDK14 or E2F2 was confirmed by dual-luciferase reporter, RNA pull-down and RNA immunoprecipitation (RIP) assays. Animal studies were used to analyze the role of circ-CDK14 in vivo. RESULTS: Our data revealed that circ-CDK14 was up-regulated and miR-198 was down-regulated in OS tissues and cell lines. Circ-CDK14 silencing suppressed OS cell viability, migration, invasion, and glycolysis and promoted cell apoptosis in vitro, as well as diminished tumor growth in vivo. Mechanistically, circ-CDK14 directly targeted miR-198. Moreover, miR-198 was a functional mediator of circ-CDK14 in regulating OS cell progression in vitro. E2F2 was a direct target of miR-198, and miR-198 overexpression regulated OS cell progression in vitro by down-regulating E2F2. Furthermore, circ-CDK14 regulated E2F2 expression by functioning as a sponge of miR-198 in OS cells. CONCLUSION: Our findings demonstrate the inhibitory effect of circ-CDK14 silencing on OS progression by targeting the miR-198/E2F2 axis, establishing a strong rationale for decreasing circ-CDK14 as a novel therapeutic strategy for OS.

Circ_0004015 silencing represses cisplatin chemoresistance and tumor progression by reducing KLF8 in a miR-198-dependent manner in non-small cell lung cancer.

Circular RNA (circRNA) plays vital roles in diverse cancer progression, including non-small cell lung cancer (NSCLC). Herein, the role of circ_0004015 in regulating the sensitivity of NSCLC to cisplatin (DDP) is revealed. The RNA expression of circ_0004015, microRNA-198 (miR-198) and kruppel like factor 8 (KLF8) was detected by quantitative real-time polymerase chain reaction. Protein expression was checked by western blot. The half maximal inhibitory concentration of DDP and cell proliferation were determined by cell counting kit-8 assay. Cell colony formation ability, migration, invasion and apoptosis were investigated by colony-forming assay, transwell assay and flow cytometry analysis, respectively. The effect of circ_0004015 knockdown on DDP sensitivity in vivo was demonstrated by mouse model assay. The interactions among circ_0004015, miR-198 and KLF8 were predicted by bioinformatics methods, and identified by mechanism assays. The expression of circ_0004015 and KLF8 was apparently upregulated, while miR-198 expression was downregulated in DDP-resistant NSCLC tissues and cells compared with control groups. Additionally, circ_0004015 silencing repressed DDP resistance, cell proliferation, migration and invasion, but induced cell apoptosis in DDP-resistant NSCLC cells. Circ_0004015 knockdown promoted the effect of DDP on tumor formation in vivo. Also, miR-198 inhibitors attenuated circ_0004015 depletion-mediated action though associating with circ_0004015. MiR-198 regulated DDP sensitivity and NSCLC progression by targeting KLF8. Furthermore, circ_0004015 modulated KLF8 expression through interaction with miR-198. Circ_0004015 conferred DDP resistance and promoted NSCLC progression by miR-198/KLF8 pathway, proving a potential target for studying DDP-mediated treatment of NSCLC.

Emerging role and function of miR-198 in human health and diseases.

Ever since their discovery, microRNAs (miRNAs/miRs) have astonished us by the plethora of processes they regulate, and thus adding another dimension to the gene regulation. They have been implicated in several diseases affecting cardiovascular, neurodegenerative, hepatic, autoimmune and inflammatory functions. A primate specific exonic miRNA, miR-198 has been vastly studied during the past decade, and shown to have a critical role in wound healing. The aberrant expression of miR-198 was first reported in schizophrenia, linking it to neural development. Later, its dysregulation and tumor suppressive role was reported in hepatocellular carcinoma. However, this was just a beginning, and after which there was an explosion of reports linking miR-198 deregulation to cancers and other ailments. The first target to be identified for miR-198 was Cyclin T1 in monocytes affecting HIV1 replication. Depending on the type of cancer, miR-198 has been shown to function either as a tumor suppressor or an oncomir. Interestingly, miR-198 is not only known to regulate multiple targets and pathways, but also is itself regulated by several circular RNAs and long-non-coding RNAs, highlighting a complex regulatory network. This review highlights the currently understood mechanism and regulation of miR-198 in different diseases, and its possible diagnostic and therapeutic potential.

Hsa_circ_0074032 promotes prostate cancer progression through elevating homeobox A1 expression by serving as a microRNA-198 decoy.

It has been reported that circular RNA hsa_circ_0074032 (circ_0074032) has a higher level in prostate cancer (PCa) tissues. However, the role and regulatory mechanism of circ_0074032 in PCa are still unknown. Circ_0074032 was overexpressed in PCa, and high circ_0074032 level was associated with worse PCa-related prognosis. Functionally, circ_0074032 silencing decreased xenograft tumour growth in vivo and induced cell apoptosis, curbed cell proliferation, migration and invasion in PCa cells in vitro. Furthermore, circ_0074032 was identified as a miR-198 decoy, and miR-198 inhibition abolished circ_0074032 silencing-mediated effects on PCa cell proliferation, apoptosis, migration and invasion. In addition, miR-198 directly targeted homeobox A1 (HOXA1), and HOXA1 weakened miR-198 mimic-mediated impacts on PCa cell malignant phenotypes. Importantly, circ_0074032 regulated HOXA1 expression by sponging miR-198. Our findings uncovered a novel mechanism by which circ_0074032 promoted PCa progression via elevating HOXA1 expression through acting as a miR-198 sponge, providing a mechanism for circ_0074032 to affect the development of PCa.

A Novel Circular RNA circPTCD3 Promotes Breast Cancer Progression Through Sponging miR-198.

INTRODUCTION: Circular RNAs (circRNAs), a new type of non-coding RNA, have been demonstrated to play critical roles in the progression of various of malignant cancers. However, the function of circRNAs in breast cancer is not clearly understood. METHODS: qPCR was used to evaluate the gene expression. Function studies including MTT, transwell, wound healing and colony formation assay were performed to evaluate the function of circPTCD3 in breast cancer. Luciferase and RNA pull-down assays were used to verify the interaction between circPTCD3 and miR-198. The xenograft model was established to evaluate the function of circPTCD3 in vivo. RESULTS: In the present study, we identified a novel circRNA termed as circPTCD3 which was indicated to be significantly up-regulated in breast cancer tissues and cell lines. The results revealed that ectopic expression of circPTCD3 promoted the cell proliferation, migration and colony formation ability of breast cancer cells. Constantly, silencing of circPTCD3 inhibited those of breast cancer cells. Furthermore, we identified that circPTCD3 was able to target miR-198 in breast cancer cell. miR-198 has the function of inhibiting proliferation and migration of breast cancer cells which can be reversed by circPTCD3. CONCLUSION: Taken together, our findings for the first time identified a novel circRNA (circPTCD3) and revealed its oncogenic role in breast cancer. Mechanically, we reported that circPTCD3 served as a competing endogenous RNA (ceRNA) to sponge miR-198. These findings provide insights into breast cancer progression and also potential new targets for diagnosis or treatment of breast cancer.

Circular RNA circ-ERBB2 promotes HER2-positive breast cancer progression and metastasis via sponging miR-136-5p and miR-198.

BACKGROUND: Circular RNAs (circRNAs) are pivotal regulators of various human cancers and circ-ERBB2 is abnormally expressed in breast cancer cells. However, the role and mechanism of circ-ERBB2 in HER2-positive breast cancer are still unknown. METHODS: The circ-ERBB2 expressions in the tumor tissues of HER2-positive breast cancer patients were tested using quantitative real-time PCR. The circ-ERBB2 function was investigated by cell counting kit 8 assay, Transwell, flow cytometry and Western blot. Mechanistically, fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull-down and dual-luciferase reporter gene assays were conducted to confirm the interaction between circ-ERBB2 and miR-136-5p or miR-198 in HER2-positive breast cancer cells. RESULTS: Circ-ERBB2 was elevated in the tumor tissues of HER2-positive breast cancer patients. Functionally, the interference with circ-ERBB2 repressed HER2-positive breast cancer cell proliferation, migration, invasion and accelerated cell apoptosis. Furthermore, the mechanistic analysis corroborated that circ-ERBB2 acted as a competing endogenous RNA for miR-136-5p or miR-198 to relieve the repressive influence of miR-136-5p or miR-198 on its target transcription factor activator protein 2C (TFAP2C). Meanwhile, in vivo assays further corroborated the oncogenic function of circ-ERBB2 in HER2-positive breast cancer. CONCLUSIONS: Circ-ERBB2 accelerated HER2-positive breast cancer progression through the circ-ERBB2/miR-136-5p/TFAP2C axis or the circ-ERBB2/miR-198/TFAP2C axis.

Circular RNA circ_0089153 acts as a competing endogenous RNA to regulate colorectal cancer development by the miR-198/SUMO-specific peptidase 1 (SENP1) axis.

Increasing evidence has indicated the implications of circular RNAs (circRNAs) in the development of colorectal cancer (CRC). In this study, we investigated the functional role and mechanism of circ_0089153 in CRC pathogenesis. The expression levels of circ_0089153, microRNA (miR)-198, and SUMO-specific peptidase 1 (SENP1) were gauged by quantitative real-time PCR (qRT-PCR) or western blot. Cell proliferation, sphere formation, tube formation, and apoptosis abilities were detected by 5-Ethynyl-2'-Deoxyuridine (EdU), sphere formation, tube formation, and flow cytometry assays, respectively. The direct relationship between miR-198 and circ_0089153 or SENP1 was verified by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. The mouse xenograft assays were performed to evaluate the role of circ_0089153 in vivo. Our data showed that circ_0089153 was overexpressed in CRC tissues and cells. Depletion of circ_0089153 repressed cell proliferation, sphere formation ability, and enhanced cell apoptosis, as well as inhibited tube formation in vitro. Moreover, circ_0089153 depletion diminished tumor growth in vivo. Mechanistically, circ_0089153 targeted miR-198, and the effects of circ_0089153 were mediated by miR-198. SENP1 was identified as a direct and functional target of miR-198. Circ_0089153 worked as a competing endogenous RNA (ceRNA) to post-transcriptionally regulate SENP1 expression by miR-198. Our findings identify circ_0089153 as a novel regulator of CRC development through the regulation of the miR-198/SENP1 axis and establish a strong rationale for developing circ_0089153 as a promising therapeutic against CRC.

Circular RNA circSP3 promotes hepatocellular carcinoma growth by sponging microRNA-198 and upregulating cyclin-dependent kinase 4.

As a new class of endogenous noncoding RNAs, circular RNAs (circRNAs), have been found to influence cell development and function by sponging microRNAs. MicroRNA (miR)-198 is downregulated in various cancers, including hepatocellular carcinoma (HCC). We therefore searched for dysregulated circRNAs that could sponge miR-198 in HCC. By analyzing relevant circRNA databases (circBase, TargetScan and CircInteractome), we found that the miR-198-binding circRNA hsa_circSP3 is upregulated in HCC. CircSP3 expression correlated negatively with miR-198 expression in HCC tissues. Dual luciferase reporter assays indicated that circSP3 bound to miR-198. CircSP3 overexpression in HCC cells induced expression of cyclin-dependent kinase 4, a target gene of miR-198. Silencing circSP3 inhibited HCC cell proliferation and migration by downregulating cyclin-dependent kinase 4, whereas inhibiting miR-198 reversed those effects. In vivo experiments confirmed that circSP3 promoted xenograft tumor growth. These data suggest that circSP3 may be a novel biomarker for HCC.

miR-198 inhibits the progression of renal cell carcinoma by targeting BIRC5.

BACKGROUND: miR-198 is involved in the formation, migration, invasion, and metastasis of various malignant cancers. However, the function and mechanism of action of miR-198 in the tumorigenesis of renal cell carcinoma (RCC) remain elusive. Here, we aimed to explore the role of miR198 in RCC. METHODS: Immunohistochemistry was performed to estimate the level of survivin in RCC sections. Quantitative real-time polymerase chain reaction was performed to determine the expression level of miR-198 in fresh RCC tissues. Furthermore, the target relationship between miR-198 and BIRC5 was predicted using the TargetScanHuman 7.2 database and verified via dual-luciferase reporter assay and western blotting. The effects of miR-198 on the viability, apoptosis, invasion, and migration of A498 and ACHN cells were studied using Cell Counting Kit-8, flow cytometry, transwell migration assay, and wound healing assay, respectively. Additionally, a xenograft nude mouse model was established to evaluate the effect of miR-198 on RCC tumorigenesis. RESULTS: The expression levels of BIRC5 and miR-198 were respectively higher and lower in RCC tissues than those in normal adjacent tissues. Furthermore, miR-198 could inhibit luciferase activity and reduce the protein level of survivin without affecting the BIRC5 mRNA levels. miR-198 inhibited cell viability, migration, and invasion and promoted cell apoptosis; co-transfection with BIRC5 could rescue these effects. Moreover, miR-198 could repress tumor growth in the xenograft nude mouse model of RCC. CONCLUSIONS: Our study demonstrates that miR-198 suppresses RCC progression by targeting BIRC5.

Hsa_circ_0010220 regulates miR-198/Syntaxin 6 axis to promote osteosarcoma progression.

BACKGROUND: Circular RNAs (circRNAs) are a class of endogenous RNAs that are involved in osteosarcoma progression. Hsa_circ_0010220 (circ_0010220) is a circRNA generated by gene Rho Guanine Nucleotide Exchange Factor 10 Like (ARHGEF10L) and is upregulated in osteosarcoma, but its functional role in osteosarcoma is limited studied. This study aimed to illustrate the regulatory mechanism underlying circ_0010220 in osteosarcoma. METHODS: 51 paired tumor and normal tissues were obtained from osteosarcoma patients. circ_0010220, microRNA (miR)-198 and Syntaxin 6 (STX6) abundances were examined by quantitative reverse transcription polymerase chain reaction and western blot. Cell proliferation, cell cycle, apoptosis, migration and invasion were analyzed via Cell Counting Kits-8 (CCK-8), colony formation, flow cytometry and transwell analyses. Target relationship was verified via dual-luciferase reporter analysis, RNA immunoprecipitation and pull-down. The in vivo function was analyzed using a xenograft model. RESULTS: Circ_0010220 was elevated in osteosarcoma tissues and cells, and was related to the lower survival rate of osteosarcoma patients. Circ_0010220 knockdown inhibited cell proliferation, migration and invasion, but induced cell cycle arrest and apoptosis in vitro. Besides, circ_0010220 silence curbed the growth of xenograft osteosarcoma tumors in vivo. Mechanistic research revealed that miR-198 is a target of circ_0010220, and directly targets STX6. Moreover, circ_0010220 upregulated the expression of STX6 by sponging miR-198 to regulate cell proliferation, migration, invasion, cell cycle, and apoptosis. CONCLUSION: Circ_0010220 contributes to osteosarcoma progression through mediating miR-198/STX6 axis, which might be a novel therapeutic target for osteosarcoma therapy.

Circ_0005198 enhances temozolomide resistance of glioma cells through miR-198/TRIM14 axis.

Circular RNAs (circRNAs) are associated with chemoresistance in many cancers. However, the function of circ_0005198 in the temozolomide (TMZ) resistance of glioma has not been well elucidated. Here, we demonstrated that circ_0005198 was considerably up-regulated in glioma tissues, serum samples and TMZ-resistant glioma cells. Silencing of circ_0005198 restrained TMZ resistance, restricted the proliferation and facilitated the apoptosis of TMZ-resistant glioma cells. MiR-198 could be sponged by circ_0005198, and we demonstrated that the effect of circ_0005198 on the progression of TMZ-resistant glioma cells was attributed to the inhibition of miR-198 activity. Moreover, TRIM14 was a target of miR-198 and silencing of TRIM14 hindered TMZ resistance and suppressed the progression of TMZ-resistant glioma cells, while TRIM14 over-expression rescued the inhibiting effect of miR-198 over-expression. We conclude that circ_0005198-miR-198-TRIM14 regulatory pathway is critical to TMZ resistance of glioma.

Circ-PRKDC Facilitates the Progression of Colorectal Cancer Through miR-198/DDR1 Regulatory Axis.

BACKGROUND: Circular RNAs (circRNAs) play a crucial role in a variety of cancers, including colorectal cancer (CRC). This study aimed to explore the role of hsa_circ_0136666 (circ-PRKDC) in CRC and its potential mechanism. METHODS: The levels of circ-PRKDC, miR-198 and discoidin domain receptor 1 (DDR1) were measured using quantitative real-time polymerase chain reaction or Western blot. Cell viability was detected using cell counting kit-8 (CCK-8) assay. Cell apoptosis and cycle were evaluated via flow cytometry. Cell migration and invasion were examined using transwell assay. CyclinD1 protein level was determined via Western blot. The interaction among circ-PRKDC, miR-198 and DDR1 was confirmed by dual-luciferase reporter assay and RNA immunoprecipitation assay. Xenograft assay was performed to analyze tumor growth in vivo. RESULTS: Circ-PRKDC and DDR1 levels were increased, and miR-198 level was decreased in CRC tissues and cells. Circ-PRKDC depletion inhibited proliferation, migration and invasion, and expedited apoptosis and cell cycle arrest in SW480 and HCT116 cells. Silence of circ-PRKDC impeded CRC progression by sponging miR-198. Overexpression of miR-198 hindered CRC development via targeting DDR1. Moreover, circ-PRKDC silencing suppressed tumor growth in vivo. CONCLUSION: Knockdown of circ-PRKDC inhibited CRC progression via modulating miR-198/DDR1 pathway.

[Study on mechanism of curcumin in treatment of acute pancreatitis based on regulation of PI3K-Akt signaling pathway by miR-198].

Curcumin was used to interfere with acute pancreatitis model rats to explore its possible mechanism. One hundred and twenty rats were randomly divided into blank group, model group, model+curcumin group, model+mock+curcumin group, model+antagonist+curcumin group and model+curcumin+LY294002 group, with 20 rats in each group. The wet/dry weight ratio of pancreatic tissue was measured and the pathological changes of pancreas were observed by HE staining. The apoptosis was detected by TUNEL staining; the levels of serum amylase, lipase, Bcl-2 and Bax were detected by ELISA, and the levels of PI3 K, Akt and p-Akt in pancreatic tissue were measured by Western blot. HE staining showed that curcumin could improve the pathological changes of pancreas and reduce the pathological score of pancreas, while ELISA results showed that curcumin could decrease the levels of amylase, lipase and Bax in peripheral serum and increase the concentration of Bcl-2. Western blot results showed that the expression levels of PI3 K and p-Akt in pancreatic tissue of model rats were up-regulated after the intervention of curcumin, and the apoptosis rate of pancreatic cells decreased in TUNEL staining. The above effects could be weakened by miR-198 antagonist and PI3 K-Akt signal pathway inhibitor LY294002. In conclusion, curcumin has an ideal effect on acute pancreatitis, and its mechanism may be mediated by miR-198-PI3 K-Akt axis.

Circular RNA LPAR3 sponges microRNA-198 to facilitate esophageal cancer migration, invasion, and metastasis.

In this study, we explored expression and functions of circular RNA LPAR3 (circLPAR3) in esophageal squamous cell carcinoma (ESCC). The differential expression of circular RNAs (circRNAs) in 10 ESCC and corresponding paracarcinoma tissues was analyzed through circRNA microarray, then the candidate circRNAs were detected and verified through quantitative RT-PCR, and a novel circRNA was screened, which was circLPAR3. Circular RNA LPAR3 showed apparently high expression in ESCC tissues and cells, which was closely correlated with the clinical stage and lymph node metastasis of ESCC patients. Circular RNA LPAR3 was mainly located in the cytoplasm of ESCC cells, which was more stable than the baseline gene. Circular RNA LPAR3 upregulated MET gene expression through sponge adsorption of microRNA (miR)-198, activated the RAS/MAPK and the PI3K/Akt pathways, and promoted ESCC cell migration, invasion, and metastasis in vivo and in vitro. However, it had no effect on ESCC cell proliferation. Circular RNA LPAR3 can regulate the miR-198-MET signal axis to promote the migration, invasion, and metastasis of esophageal cancer cells, which can thereby serve as a potential diagnostic and therapeutic target of esophageal cancer.

Circ0004390 promotes cell proliferation through sponging miR-198 in ovarian cancer.

Circular RNAs (circRNAs) are a novel class of non-coding RNAs which play important roles in human diseases and tumor progression. However, the function of circRNAs in ovarian cancer remains to be uncovered. Here we found a large amount of circRNAs that are differentially expressed in ovarian cancer tissues compared with normal ovarian tissues. We further identified one circRNA derived from the LPAR3 gene and termed Circ0004390, which was frequently upregulated in ovarian cancer tissues. The knockdown of Circ0004390 can significantly reduce the proliferation of ovarian cancer cells. We further demonstrated that Circ0004390 may promote cell proliferation by acting as a sponge for the miR-198 family to regulated the MET expression in ovarian cancer cells. The level of Circ0004390 was closely related with overall survival of ovarian cancer patients. Our findings suggested that Circ0004390 regulated ovarian cancer proliferation by miR-198/MET axis, which might provide a potential target for the treatment of ovarian cancer.

Long noncoding RNA LINC00473 functions as a competing endogenous RNA to regulate MAPK1 expression by sponging miR-198 in breast cancer.

Breast cancer (BC) is one of the primary tumors with high incidence in women. The purpose of this study was to investigate the role of LINC00473 and underlying mechanisms in BC. Expression pattern of LINC00473 was analyzed using qRT-PCR (quantitative real-time polymerase chain reaction) assays in BC tissues and cells. Overexpression or knockdown of LINC00473 in vitro and functional experiments were performed to study its effects on BC cells. Target prediction, luciferase assays, RNA fluorescence in situ hybridization and RNA immunoprecipitation were used to verify the role of LINC00473 as a competing endogenous RNA. The impact of LINC00473 on tumor growth was also evaluated using a xenograft model. In our study, we found that LINC00473 was highly expressed in BC tissues and cells, and the elevated expression was correlated with shorter overall survival in patients with BC. Furthermore, knockdown of LINC00473 significantly inhibited the capacity of proliferation, invasion and migration of BC cells. Animal experiment suggested that silencing LINC00473 could significantly inhibit the tumor growth. Following experiments revealed that LINC00473 may function as a competing endogenous RNA to regulate the expression of Mitogen-Activated Protein Kinase 1 (MAPK1) through competition for miR-198. Thus, increased expression of LINC00473 in breast cancer tissues is linked to poor prognosis. LINC00473 may function as an endogenous completive RNA by sponging miR-198 to regulate MAPK1 expression. Findings of our study contributed to the basis for further exploring the application of LINC00473 as a prognostic and diagnostic biomarker.

MicroRNA-198 inhibits proliferation and induces apoptosis by directly suppressing FGFR1 in gastric cancer.

MicroRNAs (miRNAs) are increasingly recognized as important therapeutic targets in cancer. Here we aim to investigate the role of miR-198, a broad-spectrum tumor suppressor, in gastric cancer (GC). MiR-198 overexpression was achieved by transfection of miR-198 mimics, followed by evaluation of cell viability using cell-counting kit 8. Cell cycle arrest and apoptosis were assessed by Annexin-V-FITC/Propidium Iodide (PI) staining flow cytometry respectively. The target of miR-198 was identified by bioinformatical analysis and confirmed by dual-luciferase assay, along with real-time PCR and Western blot analyses of target gene expression after transfection of miR-198 mimics. GC tissues were characterized by miR-198 down-regulation. Restoration of miR-198 expression attenuated GC cell proliferation and colony formation, meanwhile inducing significant G0/G1 arrest. Furthermore, combinatory therapy of cisplatin and miR-198 induced greater anti-tumor effects than treatment with cisplatin single therapy. We also identified fibroblast growth factor receptor 1 (FGFR1) as a direct target gene of miR-198. Furthermore, FGFR1 silencing elicited a similar tumor-suppressive effect as miR-198 overexpression. FGFR1 overexpression antagonized the anti-tumor effects of miR-198 overexpression. MiR-198/FGFR1 axis plays an important role in proliferation and apoptosis of GC. Therapies targeted to miR-198 can potentially improve GC treatment.

Circular RNA AKT3 upregulates PIK3R1 to enhance cisplatin resistance in gastric cancer via miR-198 suppression.

BACKGROUND: Cisplatin (CDDP) treatment is one of the most predominant chemotherapeutic strategies for patients with gastric cancer (GC). A better understanding of the mechanisms of CDDP resistance can greatly improve therapeutic efficacy in patients with GC. Circular RNAs (circRNAs) are a class of noncoding RNAs whose functions are related to the pathogenesis of cancer, but, in CDDP resistance of GC remains unknown. METHODS: circAKT3 (hsa_circ_0000199, a circRNA originating from exons 8, 9, 10, and 11 of the AKT3 gene) was identified by RNA sequencing and verified by quantitative reverse transcription PCR. The role of circAKT3 in CDDP resistance in GC was assessed both in vitro and in vivo. Luciferase reporter assay, biotin-coupled RNA pull-down and fluorescence in situ hybridization (FISH) were conducted to evaluate the interaction between circAKT3 and miR-198. Functional experiments were measured by western blotting, a cytotoxicity assay, clonogenic assay and flow cytometry. RESULTS: The expression of circAKT3 was higher in CDDP-resistant GC tissues and cells than in CDDP-sensitive samples. The upregulation of circAKT3 in GC patients receiving CDDP therapy was significantly associated with aggressive characteristics and was an independent risk factor for disease-free survival (DFS). Our data indicated that circAKT3 promotes DNA damage repair and inhibits the apoptosis of GC cells in vivo and in vitro. Mechanistically, we verified that circAKT3 could promote PIK3R1 expression by sponging miR-198. CONCLUSIONS: circAKT3 plays an important role in the resistance of GC to CDDP. Thus, our results highlight the potential of circAKT3 as a therapeutic target for GC patients receiving CDDP therapy.