circST6GALNAC6 suppresses bladder cancer metastasis by sponging miR-200a-3p to modulate the STMN1/EMT axis

AbstractBladder cancer (BCa) is an aggressive malignancy because of its distant metastasis and high recurrence rate. Circular RNAs (circRNAs) exert critical regulatory functions in cancer progression. However, the expression patterns and roles of circRNAs in BCa have not been well investigated. In this study, we first screened circRNA expression profiles using a circRNA microarray of paired BCa and normal tissues, and the expression of circST6GALNAC6 was confirmed by qRT-PCR and fluorescence in situ hybridization (FISH). MTT, colony formation and Transwell assays were performed to measure cell proliferation, migration and invasion. We investigated the regulatory effect of circST6GALNAC6 on miRNA and its target genes to explore the potential regulatory mechanisms of circST6GALNAC6 by chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), MS2-tagged RNA affinity purification (MS2-TRAP), immunofluorescence (IF) and dual luciferase activity assays. A nude mouse xenograft model was used to examine the functions of circST6GALNAC6/STMN1 in tumour metastasis in vivo. We found that 881 circRNAs were significantly dysregulated in BCa tissues compared to normal tissues. circST6GALNAC6(hsa_circ_0088708) was downregulated in BCa tissues and cells. Overexpression of circST6GALNAC6 effectively inhibited the cell proliferation, migration, invasion and epithelial–mesenchymal transition (EMT) in vitro and suppressed BCa metastasis in vivo. Mechanistically, we showed that the SP1 transcription factor, which binds to the circST6GALNAC6 mRNA transcript, activates circST6GALNAC6 transcription. Next, we verified that circST6GALNAC6 serves as a sponge that directly binds miR-200a-3p to regulate stathmin (STMN1) expression. Furthermore, we found that STMN1 is involved in circST6GALNAC6/miR-200a-3p axis-regulated BCa EMT and metastasis. Thus, our findings indicate an important underlying mechanism in BCa metastasis by which SP1-induced circST6GALNAC6 sponges miR-200a-3p to promote STMN1/EMT signalling. This mechanism could provide pivotal potential prognostic biomarkers and therapeutic targets for BCa.

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High LINC01605 expression predicts poor prognosis and promotes tumor progression via up-regulation of MMP9 in bladder cancer

Bioscience Reports ◽

10.1042/bsr20180562 ◽

2018 ◽

Vol 38 (5) ◽

Cited By ~ 7

Author(s):

Zhiqiang Qin ◽

Yi Wang ◽

Jingyuan Tang ◽

Lei Zhang ◽

Ran Li ◽

...

Keyword(s):

Bladder Cancer ◽

Survival Analysis ◽

Signaling Pathway ◽

High Throughput Sequencing ◽

Epithelial Mesenchymal Transition ◽

Histological Grade ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Normal Tissues

The advent of high-throughput sequencing methods has facilitated identification of novel long non-coding RNAs (lncRNAs), which have been demonstrated to play an important role in multiple tumors. Moreover, with the assistance of bioinformatics analysis, LINC01605 has been found to be up-regulated in bladder cancer (BC) tissues compared with normal tissues. Hence, the present study was to explore its specific biological role and related mechanism in BC. The relative expression level of LINC01605 was measured in a cohort of BC tissues with matched normal tissues as well as human BC cell lines by quantitative real-time PCR (qRT-PCR). Survival analysis was performed to explore the relationship between LINC01605 expression and the prognosis of BC patients. The biological function of LINC01605 was studied in vitroand in vivo, by means of CCK-8 assay, colony formation assay, transwell assay, and tumor xenografts mice model. LINC01605 was found to be frequently highly expressed in both human BC cells and tissues. Survival analysis indicated that high LINC01605 expression was associated with higher histological grade and clinical stages. In addition, down-regulated LINC01605 in BC cells could significantly inhibit the abilities of proliferation, migration, and invasion in vitro and knockdown of LINC01605 in subcutaneous xenograft tumor model could impede tumorigenesis in vivo. Mechanistically, LINC01605 could activate epithelial–mesenchymal transition (EMT) signaling pathway and promote the expression of matrix metallopeptidase (MMP) 9 (MMP9). In summary, our results shed light on that LINC01605, as a new prognostic biomarker, could promote the proliferation, migration, and invasion of BC cells via activating EMT signaling pathway and up-regulating MMP9 expression.

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Upregulation of Long Non-Coding RNA PlncRNA-1 Promotes Metastasis and Induces Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma

Cellular Physiology and Biochemistry ◽

10.1159/000443038 ◽

2016 ◽

Vol 38 (2) ◽

pp. 836-846 ◽

Cited By ~ 24

Author(s):

Liyang Dong ◽

Junwei Ni ◽

Wenhao Hu ◽

Chang Yu ◽

Haiyan Li

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Epithelial Mesenchymal Transition ◽

Clinicopathological Characteristics ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Normal Tissues ◽

Promote Tumor Growth

Background/Aims: PlncRNA-1 has been demonstrated to promote malignancy in various cancers. The present study aims to investigate the expression pattern, prognosis value and the function of PlncRNA-1 in human hepatocellular carcinoma (HCC). Methods: The expression of PlncRNA-1 in 84 pairs of HCC and their matched normal tissues was examined by quantitative real-time polymerase chain reaction (qRT-PCR). The correlations of PlncRNA-1 expression and clinicopathological characteristics and prognosis were also analyzed. The biological role of PlncRNA-1 in cell proliferation, migration and invasion was examined in vitro and in vivo. Results: The results showed that the level of PlncRNA-1 expression was significantly increased in HCC tissues and significantly correlated with tumor size, vascular invasion and advanced TNM stage. Moreover, patients with high levels of PlncRNA-1 expression had relatively poor prognostic outcomes, serving as an independent prognostic factor for HCC. In vitro functional assays indicated that knockdown of PlncRNA-1 expression significantly reduced cell proliferation, migration and invasion by inhibiting the epithelial-mesenchymal transition (EMT) signaling. Animal model experiments confirmed the ability of PlncRNA-1 to promote tumor growth in vivo. Conclusions: Taken together, our findings suggest that PlncRNA-1 may serve as an oncogene in HCC progression and represent a valuable prognostic marker and potential therapeutic target for HCC.

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Circular RNA hsa_circ_101555 promotes hepatocellular carcinoma cell proliferation and migration by sponging miR-145-5p and regulating CDCA3 expression

Cell Death and Disease ◽

10.1038/s41419-021-03626-7 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Xiaoguang Gu ◽

Jianan Zhang ◽

Yajuan Ran ◽

Hena Pan ◽

JinHong Jia ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Biological Effects ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Casein Kinase 1 ◽

Mouse Xenograft Model ◽

Hcc Cells

AbstractCircular RNAs have been reported to play significant roles in regulating pathophysiological processes while also guiding clinical diagnosis and treatment of hepatocellular carcinoma (HCC). However, only a few circRNAs have been identified thus far. Herein, we investigated the role of a specific closed-loop structure of hsa_circ_101555 that was generated by back-splicing of the host gene casein kinase 1 gamma 1 (CSNK1G1) in the development and proliferation of HCC. We investigated the expression of Hsa_circ_101555 in HCC and normal tissues using bioinformatics. The expression level of hsa_circ_101555 was further detected by fluorescence in situ hybridization and qRT-PCR in ten HCC patients. Transwell, migration, WST-1 assays, and colony formation assays were used to evaluate the role of hsa_circ_101555 in HCC development and proliferation. The regulatory mechanisms of hsa_circ_101555 in miR-145-5p and CDCA3 were determined by dual luciferase reporter assay. A mouse xenograft model was also used to determine the effect of hsa_circ_101555 on HCC growth in vivo. hsa_circ_101555 showed greater stability than the linear RNA; while in vitro and in vivo results demonstrated that hsa_circ_101555 silencing significantly suppressed cell proliferation, migration, and invasion of HCC cells. Rescue experiments further demonstrated that suppression of miR-145-5p significantly attenuated the biological effects of hsa_circ_101555 knockdown in HCC cells. We also identified a putative oncogene CDCA3 as a potential miR-145-5p target. Thus, our results demonstrated that hsa_circ_101555 might function as a competing endogenous RNA of miR-145-5p to upregulate CDCA3 expression in HCC. These findings suggest that hsa_circ_101555 may be a potential therapeutic target for patients with HCC.

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Knockdown of ARK5 Expression Suppresses Invasion and Metastasis of Gastric Cancer

Cellular Physiology and Biochemistry ◽

10.1159/000478685 ◽

2017 ◽

Vol 42 (3) ◽

pp. 1025-1036 ◽

Cited By ~ 12

Author(s):

Dehu Chen ◽

Guiyuan Liu ◽

Ning Xu ◽

Xiaolan You ◽

Haihua Zhou ◽

...

Keyword(s):

Gastric Cancer ◽

Western Blot ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Migration And Invasion ◽

Invasion And Metastasis ◽

Ags Cells ◽

Mesenchymal Transition

Background/Aims: Gastric cancer (GC) is a common and lethal malignancy, and AMP-activated protein kinase-related kinase 5 (ARK5) has been discovered to promote cancer metastasis in certain types of cancer. In this study, we explored the role of ARK5 in GC invasion and metastasis. Methods: ARK5 and epithelial-mesenchymal transition (EMT)-related markers were determined by immunohistochemistry and western blot in GC specimens. Other methods including stably transfected against ARK5 into SGC7901 and AGS cells, western blot, migration and invasion assays in vitro and nude mice tumorigenicity in vivo were also employed. Results: The results demonstrated that ARK5 expression was increased and positively correlated with metastasis, EMT-related markers and poor prognosis in patients with GC. Knockdown of ARK5 expression remarkably suppressed GC cells invasion and metastasis via regulating EMT, rather than proliferation in vitro and in vivo. And knockdown of ARK5 expression in GC cells resulted in the down-regulation of the mTOR/p70S6k signals, Slug and SIP1. Conclusion: The elevated ARK5 expression was closely associated with cancer metastasis and patient survival, and it seemed to function in GC cells migration and invasion via EMT alteration, together with the alteration of the mTOR/p70S6k signals, Slug and SIP1, thus providing a potential therapeutic target for GC.

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RBFOX3 Regulates the Chemosensitivity of Cancer Cells to 5-Fluorouracil via the PI3K/AKT, EMT and Cytochrome-C/Caspase Pathways

Cellular Physiology and Biochemistry ◽

10.1159/000489153 ◽

2018 ◽

Vol 46 (4) ◽

pp. 1365-1380 ◽

Cited By ~ 5

Author(s):

Tianze Liu ◽

Xiaojun Wu ◽

Yizhuo Li ◽

Wenjing Lu ◽

Fufu Zheng ◽

...

Keyword(s):

Cell Proliferation ◽

Cytochrome C ◽

Rna Binding ◽

Inhibitory Effect ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Mouse Xenograft ◽

Mouse Xenograft Model ◽

Hcc Cells

Background/Aims: RBFOX3, an RNA-binding fox protein, plays an important role in the differentiation of neuronal development, but its role in the chemosensitivity of hepatocellular carcinoma (HCC) to 5-FU is unknown. Methods: In this study, we examined the biological functions of RBFOX3 and its effect on the chemosensitivity of HCC cells to 5-FU in vitro and in a mouse xenograft model. Results: RBFOX3 was found to have elevated expression in HCC cell lines and tissue samples, and its knockdown inhibited HCC cell proliferation. Moreover, knockdown of RBFOX3 improved the inhibitory effect of 5-fluorouracil (5-FU) on cell proliferation, migration and invasion, and enhanced the apoptosis induced by 5-FU. However, overexpression of RBFOX3 reduced the inhibitory effect of 5-fluorouracil (5-FU) on cell proliferation, migration and invasion, and decreased the apoptosis induced by 5-FU. We further elucidated that RBFOX3 knockdown synergized with 5-FU to inhibit the growth and invasion of HCC cells through PI3K/AKT and epithelial-mesenchymal transition (EMT) signaling, and promote apoptosis by activating the cytochrome-c/caspase signaling pathway. Finally, we validated that RBFOX3 regulated 5-FU-mediated cytotoxicity in HCC in mouse xenograft models. Conclusions: The findings from this study indicate that RBFOX3 regulates the chemosensitivity of HCC to 5-FU in vitro and in vivo. Therefore, targeting RBFOX3 may improve the inhibition of HCC growth and progression by 5-FU, and provide a novel potential therapeutic strategy for HCC.

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lncRNA TUG1-Mediated Mir-142-3p Downregulation Contributes to Metastasis and the Epithelial-to-Mesenchymal Transition of Hepatocellular Carcinoma by Targeting ZEB1

Cellular Physiology and Biochemistry ◽

10.1159/000492517 ◽

2018 ◽

Vol 48 (5) ◽

pp. 1928-1941 ◽

Cited By ~ 27

Author(s):

Chuan He ◽

Zhigang Liu ◽

Li Jin ◽

Fang Zhang ◽

Xinhao Peng ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Cell Migration ◽

Noncoding Rna ◽

Epithelial Mesenchymal Transition ◽

Tumor Formation ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Mesenchymal Transition

Background/Aims: MicroRNA-142-3p (miR-142-3p) is dysregulated in many malignancies and may function as a tumor suppressor or oncogene in tumorigenesis and tumor development. However, few studies have investigated the clinical significance and biological function of miR-142-3p in hepatocellular carcinoma (HCC). Methods: The expression levels of taurine upregulated gene 1 (TUG1), miR-142-3p, and zinc finger E-box-binding homeobox 1 (ZEB1) were evaluated in HCC tissues and cell lines by quantitative real-time PCR. MTT and colony formation assays were used to detect cell proliferation ability, transwell assays were used to assess cell migration and invasion, and luciferase reporter assays were used to examine the interaction between the long noncoding RNA TUG1 and miR-142-3p. Tumor formation was evaluated through in vivo experiments. Results: miR-142-3p was significantly downregulated in HCC tissues, but TUG1 was upregulated in HCC tissues. Knockdown of TUG1 and upregulation of miR-142-3p inhibited cell proliferation, cell migration, cell invasion, and the epithelial-mesenchymal transition (EMT). miR-142-3p was found to be a prognostic factor of HCC, and the mechanism by which TUG1 upregulated ZEB1 was via direct binding to miR-142-3p. In vivo assays showed that TUG1 knockdown suppressed cell proliferation and the EMT in nude mice. Conclusion: The results of this study suggest that the TUG1/miR-142-3p/ ZEB1 axis contributes to the formation of malignant behaviors in HCC.

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MicroRNA-99b predicts clinical outcome of osteosarcoma and suppresses tumor cell proliferation, migration and invasion

Diagnostic Pathology ◽

10.1186/s13000-019-0889-y ◽

2019 ◽

Vol 14 (1) ◽

Cited By ~ 1

Author(s):

Xin Shi ◽

Xingfa Guan

Keyword(s):

Cell Proliferation ◽

Cell Lines ◽

Prognostic Value ◽

Cox Regression ◽

Expression Profiles ◽

Migration And Invasion ◽

Aberrant Expression ◽

Cox Regression Analysis ◽

Normal Tissues

Abstract Background Osteosarcoma (OS) is a malignancy predominantly occurred in children and adolescents. Numerous microRNAs are involved in the pathogenesis of various cancers. This study aimed to investigate the expression profiles of miR-99b and its prognostic value in OS patients, and further analyze the biological function of miR-99b in the tumor progression by using OS cells. Methods Expression of miR-99b was measured using quantitative real-time PCR. Kaplan-Meier survival curves and Cox regression analysis were performed to evaluate the prognostic value of miR-99b. OS cell lines were used to investigate the effects of miR-99b on cell proliferation, migration and invasion. Results A significant decreased expression of miR-99b was observed in the OS tissues and cell lines respectively compared with the normal tissues and cells. Aberrant expression of miR-99b was associated with the patients’ metastasis and TNM stage, and could be used to predict the prognosis of OS. The expression of miR-99b was regulated in vitro by cell transfection, and we found that the overexpression of miR-99b led to suppressed cell proliferation, migration and invasion, whereas the knockdown of miR-99b resulted in the opposite results. Conclusions In one word, the aberrantly expressed miR-99b serves a prognostic biomarker for OS patients. OS cell proliferation, migration and invasion can be inhibited by the overexpression of miR-99b, suggesting that the methods to increase miR-99b expression may be novel therapeutic strategies in OS.

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LINC00460 / DHX9/IGF2BP2 complex promotes colorectal cancer proliferation and metastasis by mediating HMGA1 mRNA stability depending on m6A modification

10.21203/rs.3.rs-103647/v1 ◽

2020 ◽

Author(s):

Pingfu Hou ◽

Sen Meng ◽

Minle Li ◽

Tian Lin ◽

Sufang Chu ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Molecular Mechanism ◽

Mrna Stability ◽

Functional Characterization ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Hmga1 Expression

Abstract Background: Increasing studies have shown that long noncoding RNAs (lncRNAs) are pivotal regulators participating in carcinogenic progression and tumor metastasis in colorectal cancer (CRC). Although lncRNA long intergenic noncoding RNA 460 (LINC00460) has been reported in CRC, the role and molecular mechanism of LINC00460 in CRC progression still requires exploration.Methods: The expression levels of LINC00460 were analyzed by using a tissue microarray containing 498 CRC tissues and their corresponding non-tumor adjacent tissues. The correlations between the LINC00460 expression level and clinicopathological features were evaluated. The functional characterization of the role and molecular mechanism of LINC00460 in CRC was investigated through a series of in vitro and in vivo experiments.Results: LINC00460 expression was increased in human CRC, and high LINC00460 expression was correlated with poor five-year overall survival and disease-free survival. LINC00460 overexpression sufficiently induced the epithelial–mesenchymal transition and promoted tumor cell proliferation, migration, and invasion in vitro and tumor growth and metastasis in vivo. In addition, LINC00460 enhanced the protein expression of high-mobility group AT-hook 1 (HMGA1) by directly interacting with IGF2BP2 and DHX9 to bind the 3′ untranslated region (UTR) of HMGA1 mRNA and increased the stability of HMGA1 mRNA. In addition, the N6-methyladenosine (m6A) modification of HMGA1 mRNA by METTL3 enhanced HMGA1 expression in CRC. Finally, it suggested that HMGA1 was essential for LINCC046-induced cell proliferation, migration, and invasion.Conclusions: LINC00460 may be a novel oncogene of CRC through interacting with IGF2BP2 and DHX9 and bind to the m6A modified HMGA1 mRNA to enhance the HMGA1 mRNA stability. LINC00460 can serve as a promising predictive biomarker for the diagnosis and prognosis among patients with CRC.

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SLC25A21 Suppresses Cell Growth in Bladder Cancer Via The Reactive Oxygen Species-Mediated Mitochondrion-Dependent Apoptosis Pathway

10.21203/rs.3.rs-154355/v1 ◽

2021 ◽

Author(s):

Yong Wang ◽

Jiawen Gao ◽

Shasha Hu ◽

Weiting Zeng ◽

Hongjun Yang ◽

...

Keyword(s):

Bladder Cancer ◽

Treatment Strategies ◽

Migration And Invasion ◽

Loss Of Function ◽

Apoptosis Pathway ◽

Normal Tissues ◽

Induced Apoptosis ◽

New Diagnosis

Abstract Background: Bladder cancer (BCa) is a commonly diagnosed malignancy worldwide that has poor survival depending on its intrinsic biologic aggressiveness and a peculiar radio- and chemoresistance features. Gaining a better understanding of tumorigenesis and developing new diagnosis and treatment strategies for BCa is important for improving BCa clinical outcome. SLC25 family member 21 (SLC25A21), a carrier transporting C5-C7 oxodicarboxylates, has been reported to contribute to oxoadipate acidemia. However, the potential role of SLC25A21 in cancer remains absolutely unknown. Methods: The expression levels of SLC25A21 in BCa and normal tissues were examined by real-time PCR and immunohistochemistry. Gain-of- and loss-of-function experiments were performed to detect the biological functions of SLC25A21 in vitro and in vivo by CCK-8 assay, plate colony formation assay, cell migration, invasion assay and experimental animal models. The subcellular distribution of substrate mediated by SLC25A21, mitochondrial membrane potential and ROS production were assessed to explore the potential mechanism of SLC25A21 in BCa.Results: We found that the expression of SLC25A21 was downregulated in BCa tissues compared to normal tissues. A significant positive correlation between decreased SLC25A21 expression and poor prognosis was observed in BCa patients. Overexpression of SLC25A21 significantly inhibited cell proliferation, migration and invasion and induced apoptosis in vitro. Moreover, the enhanced SLC25A21 expression significantly suppressed tumor growth in a xenograft mouse model. Furthermore, we revealed that SLC25A21 suppressed BCa growth by inducing the efflux of mitochondrial α-KG to the cytosol, decreasing to against oxidative stress, and activating the ROS-mediated mitochondrion-dependent apoptosis pathway. Conclusions: Our findings provide the first link between SLC25A21 expression and BCa and demonstrate that SLC25A21 acts as a crucial suppressor in BCa progression, which may help to provide new targets for BCa intervention.

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LncRNA LEF1-AS1 promotes metastasis of prostatic carcinoma via the Wnt/β-catenin pathway

10.21203/rs.3.rs-40046/v3 ◽

2020 ◽

Author(s):

Weiyuan Li ◽

Ganggang Yang ◽

Dengke Yang ◽

Dong Li ◽

Qian Sun

Keyword(s):

Cell Proliferation ◽

Migration And Invasion ◽

Biological Processes ◽

Sequencing Technology ◽

Next Generation Sequencing Technology ◽

Normal Tissues ◽

Factor C ◽

Generation Sequencing

Abstract Background Long noncoding RNAs (lncRNAs), which are important functional regulators in cancer, have emerged as critical molecular regulators in various biological processes. However, the mechanisms by which LEF1-AS1 modulates Androgen-Independent Prostate Cancer (AIPC) development remain largely unknown. Methods The LEF1-AS1 expression level was detected in tumour tissues and adjacent normal tissues of AIPC patients by using next-generation sequencing technology and qRT-PCR. Cell proliferation, migration and invasion were assessed by colony formation, EDU assays and transwell assays, respectively. Xenograft assay was conducted to determine the effect of LEF1-AS1 on cell proliferation in vivo. Results LEF1-AS1 promoted the proliferation, migration, invasion and angiogenic ability of AIPC cells in vitro and in vivo. In this mechanism, LEF1-AS1 recruited the transcription factor C-myb to the promoter region of FZD2, which activated FZD2 transcription. Moreover, LEF1-AS1 functioned as a competing endogenous RNA (ceRNA) acting as a sponge for miR-328, which activated CD44. Conclusion Collectively, these data indicate that LEF1-AS1 is a tumour promoter in the development of AIPC and that it may contribute to the improvement of AIPC diagnosis and therapy.

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