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

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.

Download Full-text

SLC25A21 Suppresses Cell Growth in Bladder Cancer via an Oxidative Stress-Mediated Mechanism

Frontiers in Oncology ◽

10.3389/fonc.2021.682710 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yong Wang ◽

Jiawen Gao ◽

Shasha Hu ◽

Weiting Zeng ◽

Hongjun Yang ◽

...

Keyword(s):

Oxidative Stress ◽

Bladder Cancer ◽

Treatment Strategies ◽

Migration And Invasion ◽

Loss Of Function ◽

Apoptosis Pathway ◽

Normal Tissues ◽

Induced Apoptosis

BackgroundBladder 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.MethodsThe 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.ResultsWe 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.ConclusionsOur 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.

Download Full-text

Long non-coding RNA SLC2A1-AS1 induced by GLI3 promotes aerobic glycolysis and progression in esophageal squamous cell carcinoma by sponging miR-378a-3p to enhance Glut1 expression

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-02081-8 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Hongtao Liu ◽

Qing Zhang ◽

Yinsen Song ◽

Yibin Hao ◽

Yunxia Cui ◽

...

Keyword(s):

Aerobic Glycolysis ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Loss Of Function ◽

Metabolic Remodeling ◽

Glut1 Expression ◽

Regulatory Feedback Loop ◽

Induced Apoptosis

Abstract Background Emerging evidence demonstrates that lncRNAs play pivotal roles in tumor energy metabolism; however, the detailed mechanisms of lncRNAs in the regulation of tumor glycolysis remain largely unknown. Methods The expression of SLC2A1-AS1 was investigated by TCGA, GEO dataset and qRT-PCR. The binding of GLI3 to SLC2A1-AS1 promoter was detected by Luciferase Reporter Assay System and Ago2-RIP assay. FISH was performed to determine the localization of SLC2A1-AS1 in ESCC cells. Double Luciferase Report assay was used to investigate the interaction of miR-378a-3p with SLC2A1-AS1 and Glut1. Gain-of-function and Loss-of-function assay were performed to dissect the function of SLC2A1-AS1/miR-378a-3p/Glut1 axis in ESCC progression in vitro and in vivo. Results We identified a novel lncRNA SLC2A1-AS1 in ESCC. SLC2A1-AS1 was frequently overexpressed in ESCC tissues and cells, and its overexpression was associated with TNM stage, lymph node metastasis and poor prognosis of ESCC patients. Importantly, GLI3 and SLC2A1-AS1 formed a regulatory feedback loop in ESCC cells. SLC2A1-AS1 promoted cell growth in vitro and in vivo, migration and invasion, and suppressed apoptosis, leading to EMT progression and increased glycolysis in ESCC cells. SLC2A1-AS1 functioned as ceRNA for sponging miR-378a-3p, resulting in Glut1 overexpression in ESCC cells. MiR-378a-3p inhibited cell proliferation and invasion as well as induced apoptosis, resulting in reduced glycolysis, which was partly reversed by SLC2A1-AS1 or Glut1 overexpression in ESCC cells. Conclusion SLC2A1-AS1 plays important roles in ESCC development and progression by regulating glycolysis, and SLC2A1-AS1/miR-378a-3p/Glut1 regulatory axis may be a novel therapeutic target in terms of metabolic remodeling of ESCC patients.

Download Full-text

RBMX suppresses tumorigenicity and progression of bladder cancer by interacting with the hnRNP A1 protein to regulate PKM alternative splicing

Oncogene ◽

10.1038/s41388-021-01666-z ◽

2021 ◽

Author(s):

Qiuxia Yan ◽

Peng Zeng ◽

Xiuqin Zhou ◽

Xiaoying Zhao ◽

Runqiang Chen ◽

...

Keyword(s):

Bladder Cancer ◽

Alternative Splicing ◽

Rna Binding ◽

Aerobic Glycolysis ◽

Histological Grade ◽

Migration And Invasion ◽

Binding Motif ◽

Hnrnp A1

AbstractThe prognosis for patients with metastatic bladder cancer (BCa) is poor, and it is not improved by current treatments. RNA-binding motif protein X-linked (RBMX) are involved in the regulation of the malignant progression of various tumors. However, the role of RBMX in BCa tumorigenicity and progression remains unclear. In this study, we found that RBMX was significantly downregulated in BCa tissues, especially in muscle-invasive BCa tissues. RBMX expression was negatively correlated with tumor stage, histological grade and poor patient prognosis. Functional assays demonstrated that RBMX inhibited BCa cell proliferation, colony formation, migration, and invasion in vitro and suppressed tumor growth and metastasis in vivo. Mechanistic investigations revealed that hnRNP A1 was an RBMX-binding protein. RBMX competitively inhibited the combination of the RGG motif in hnRNP A1 and the sequences flanking PKM exon 9, leading to the formation of lower PKM2 and higher PKM1 levels, which attenuated the tumorigenicity and progression of BCa. Moreover, RBMX inhibited aerobic glycolysis through hnRNP A1-dependent PKM alternative splicing and counteracted the PKM2 overexpression-induced aggressive phenotype of the BCa cells. In conclusion, our findings indicate that RBMX suppresses BCa tumorigenicity and progression via an hnRNP A1-mediated PKM alternative splicing mechanism. RBMX may serve as a novel prognostic biomarker for clinical intervention in BCa.

Download Full-text

CircLDLR Promotes Papillary Thyroid Carcinoma Tumorigenicity by Regulating miR-637/LMO4 Axis

Disease Markers ◽

10.1155/2021/3977189 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Yuan-ming Jiang ◽

Wei Liu ◽

Ling Jiang ◽

Hongbin Chang

Keyword(s):

Papillary Thyroid Carcinoma ◽

Thyroid Carcinoma ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Migration And Invasion ◽

Circular Rnas ◽

Papillary Thyroid ◽

Induced Apoptosis

Background. Circular RNAs (circRNAs) have been reported to play important roles in the development and progression of papillary thyroid carcinoma (PTC). However, the function and molecular mechanism of circRNA low-density lipoprotein receptor (circLDLR) in the tumorigenesis of PTC remain unknown. Results. In this study, circLDLR was found to be markedly upregulated in PTC tissues and cell lines, and knockdown of circLDLR inhibited PTC cell proliferation, migration, and invasion but induced apoptosis in vitro. Moreover, circLDLR acted as a sponge for miR-637, and miR-637 interference reversed the anticancer effects of circLDLR knockdown on PTC cells. LMO4 was verified to be a target of miR-637; LMO4 upregulation abolished miR-637 mediated inhibition of cell growth and metastasis in PTC. Additionally, circLDLR could indirectly modulate LMO4 via acting as a sponge of miR-637 in PTC cells. Besides that, xenograft analysis showed that circLDLR knockdown suppressed tumor growth in vivo via regulating LMO4 and miR-637. Conclusion. Taken together, these results demonstrated that circLDLR promoted PTC tumorigenesis through miR-637/LMO4 axis, which may provide a novel insight into the understanding of PTC tumorigenesis and be useful in developing potential targets for PTC treatment.

Download Full-text

CircRNA circ-ERBB2 elevates Warburg effect and facilitates triple-negative breast cancer growth by the miR-136-5p/PDK4 axis

Molecular and Cellular Biology ◽

10.1128/mcb.00609-20 ◽

2021 ◽

Author(s):

Yihong Huang ◽

Shuo Zheng ◽

Ying Lin ◽

Liming Ke

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Warburg Effect ◽

Triple Negative ◽

Pyruvate Dehydrogenase Kinase ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Loss Of Function

Triple negative breast cancer (TNBC) is an aggressive histological subtype of breast cancer. It has been reported that that circRNA circ-ERBB2 (circBase ID: hsa_circ_0007766) is mainly distributed in the cytoplasm of TNBC cells and promotes the proliferation and invasion of TNBC cells. This study aimed to explore the molecular mechanism of circ-ERBB2 regulating the progression of TNBC. Expression of circ-ERBB2 was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Loss-of-function experiments were performed to investigate the function of circ-ERBB2 in TNBC cells in vitro and in vivo . The regulatory mechanism of circ-ERBB2 was surveyed by bioinformatics analysis, dual-luciferase reporter and RNA immunoprecipitation (RIP) or RNA pull-down assays. We observed that Circ-ERBB2 was overexpressed in TNBC, and TNBC patients with high circ-ERBB2 expression had a poor prognosis. Functionally, circ-ERBB2 knockdown constrained TNBC growth in vivo and reduced Warburg effect, accelerated apoptosis, repressed proliferation, migration, and invasion of TNBC cell in vitro . Mechanically, circ-ERBB2 sponged miR-136-5p to elevate pyruvate dehydrogenase kinase 4 (PDK4) expression. In conclusion, circ-ERBB2 facilitated Warburg effect and malignancy of TNBC cells by the miR-136-5p/PDK4 pathway, at least in part. This study supported circ-ERBB2 as a prognostic indicator for TNBC.

Download Full-text

circLMTK2 acts as a sponge of miR-150-5p and promotes proliferation and metastasis in gastric cancer

Molecular Cancer ◽

10.1186/s12943-019-1081-4 ◽

2019 ◽

Vol 18 (1) ◽

Cited By ~ 15

Author(s):

Sen Wang ◽

Dong Tang ◽

Wei Wang ◽

Yining Yang ◽

Xiaoqing Wu ◽

...

Keyword(s):

Gastric Cancer ◽

Bioinformatic Analysis ◽

Migration And Invasion ◽

Circular Rnas ◽

Normal Tissues ◽

Tumour Metastasis ◽

Genome Wide ◽

Proliferation And Metastasis

Abstract Background As a novel class of non-coding RNAs, circular RNAs (circRNAs) are key regulators of the development and progression of different cancers. However, little is known about the function and biological mechanism of circLMTK2, also named hsa_circ_0001725, in gastric cancer (GC) tumourigenesis. Methods circLMTK2 was identified in ten paired cancer specimens and adjacent normal tissues by RNA sequencing and genome-wide bioinformatic analysis and verified by quantitative real-time PCR (qRT-PCR). Knockdown or exogenous expression of circLMTK2 combined with in vitro and in vivo assays were performed to prove the functional significance of circLMTK2. The molecular mechanism of circLMTK2 was demonstrated by searching the CircNet database and confirmed by RNA in vivo precipitation assays, western blotting, luciferase assays and rescue experiments. Results circLMTK2 was frequently upregulated in GC tissues, and high circLMTK2 expression was associated with poor prognosis, lymph node metastasis and poor TNM stage in GC patients. Functionally, circLMTK2 overexpression promoted GC cell proliferation and tumourigenicity in vitro and in vivo. Furthermore, ectopic circLMTK2 expression enhanced GC cell migration and invasion in vitro and tumour metastasis in vivo. In addition, we demonstrated that circLMTK2 could sponge miR-150-5p, thus indirectly regulating the c-Myc expression and contributing to GC tumourigenesis. Conclusion Our findings demonstrate that circLMTK2 functions as a tumour promoter in GC through the miR-150-5p/c-Myc axis and could thus be a prognostic predictor and therapeutic target for GC.

Download Full-text

RACK1 Acts as a Potential Tumor Promoter in Colorectal Cancer

Gastroenterology Research and Practice ◽

10.1155/2019/5625026 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8

Author(s):

Xue-Yang Li ◽

Yi Hu ◽

Nian-Shuang Li ◽

Jian-Hua Wan ◽

Yin Zhu ◽

...

Keyword(s):

Colorectal Cancer ◽

The Cancer Genome Atlas ◽

Biological Role ◽

Tumor Promoter ◽

Migration And Invasion ◽

Loss Of Function ◽

Normal Tissues ◽

Geo Dataset

Background. The receptor of activated protein kinase C 1 (RACK1) promotes the progression and invasion of several cancers. However, the role of RACK1 in the pathogenesis of colorectal cancer (CRC) has not been clearly defined. Herein, we aimed to investigate the biological role of RACK1 in CRC. Materials and Methods. The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) dataset were searched, and the expression of RACK1 in CRC tissues and adjacent normal tissues was evaluated. Immunohistochemical staining was performed to detect the expression of RACK1 in human CRC, adenoma, and normal tissues. Western blotting was used to detect the expression of RACK1 in human CRC cell lines. Functional assays, such as BrdU, colony formation, and wound healing and transwell invasion assays, were used to explore the biological role of RACK1 in CRC. Results. RACK1 was upregulated in CRC tissues compared with its expression in adjacent normal tissues in TCGA and the GEO dataset (P<0.05). Moreover, RACK1 was significantly overexpressed in CRC and adenoma tissues compared with its expression in normal tissues (P<0.05). Loss-of-function experiments showed that RACK1 promoted cell proliferation, migration, and invasion in vitro. Conclusions. Our data indicated that RACK1, as an oncogene, markedly promoted the progression of CRC, which suggested that RACK1 is a potential therapeutic target for CRC management.

Download Full-text

Upregulated TRIM11 Exerts its Oncogenic Effects in Hepatocellular Carcinoma Through Inhibition of P53

Cellular Physiology and Biochemistry ◽

10.1159/000484678 ◽

2017 ◽

Vol 44 (1) ◽

pp. 255-266 ◽

Cited By ~ 10

Author(s):

Jinjin Liu ◽

Jun Rao ◽

Xuming Lou ◽

Jian Zhai ◽

Zhenhua Ni ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Development ◽

Tumor Model ◽

Migration And Invasion ◽

P53 Expression ◽

Protein Levels ◽

Normal Tissues ◽

P53 Signaling

Background/Aims: The tripartite motif containing (TRIM) family plays crucial roles in tumor development and progression. However, little is known about the function and mechanism of TRIM11 in hepatocellular carcinoma (HCC). Methods: The expression levels of TRIM11 were examined by real-time PCR, Western blot and Immunohistochemical (IHC) staining. TRIM11 knockdown cells were produced by lentivirus infection, and functional assays, such as MTT, colony formation assay, migration and invasion assays and a xenograft tumor model were used to investigate the role of TRIM11 in HCC. We also determined the effect of TRIM11 on p53 signaling and its downstream molecules. Results: We found that TRIM11 mRNA and protein levels were significantly increased in HCC tissues as compared with normal tissues; increased levels correlated with poor patient survival. By loss- and gain-of-function investigations, knockdown of TRIM11 suppressed cell proliferation, migration, invasion in vitro and tumor growth in vivo. Moreover, TRIM11 negatively regulated p53 expression. Knockdown of p53 abrogated the in vitro and in vivo biological functions of TRIM11 shRNA in HCC cells. Conclusions: These data show that TRIM11 exerts its oncogenic effect in HCC by downregulating p53 both in vitro and in vivo. Our data provide new insights into the pathogenesis of HCC and indicate that TRIM11 may serve as a new therapeutic target for HCC treatment.

Download Full-text

AIMP2-DX2 Promotes the Proliferation, Migration, and Invasion of Nasopharyngeal Carcinoma Cells

BioMed Research International ◽

10.1155/2018/9253036 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 3

Author(s):

Qingsong Cao ◽

Jie Zhang ◽

Tao Zhang

Keyword(s):

Nasopharyngeal Carcinoma ◽

Protein Expression ◽

Southern China ◽

Immunohistochemical Analysis ◽

Prognostic Indicator ◽

Trna Synthetase ◽

Migration And Invasion ◽

Induced Apoptosis

Nasopharyngeal carcinoma (NPC) is a head and neck tumor with high degree of malignancy and with high incidence especially in southern China. AIMP2-DX2, one isoform of the aminoacyl-tRNA synthetase interacting multifunctional proteins (AIMPs), is shown to be a potential target in many cancers. However, the detailed mechanisms of AIMP2-DX2 in NPC development remain to be elucidated. Here, we found that the mRNA expression level of AIMP2-DX2 was significantly increased in NPC specimens, compared with normal nasopharyngeal tissues. Microarray immunohistochemical analysis of NPC specimens and Kaplan–Meier analysis showed that patients with high AIMP2-DX2 protein expression had shorter overall survival than those with low AIMP2-DX2 level. Furthermore, mRNA and protein expression levels of AIMP2-DX2 were both increased in cultured NPC cell lines (5-8F, CNE-2Z, and CNE-1), by being compared with normal nasopharyngeal cell line NP69. Overexpression of AIMP2-DX2 remarkably promoted the cell viability, cell migration, and invasion of cultured NPC cells. Genetic knockdown of AIMP2-DX2 by shRNA lentiviruses significantly suppressed the proliferation, migration, and invasion and induced apoptosis of NPC cells. Inhibition of AIMP2-DX2 decreased the highly expressed level of matrix metalloproteinase- (MMP-) 2 and MMP-9, further suppressed proliferation, migration, and invasion in cultured NPC cells in vitro, and inhibited tumor growth in a xenograft mouse model in vivo. Taken together, these results suggest that AIMP2-DX2 plays an important role in the regulation of NPC and could be a potential therapeutic target and prognostic indicator for the treatment of NPC.

Download Full-text

Circ-ZFR Promotes Progression of Bladder Cancer by Upregulating WNT5A Via Sponging miR-545 and miR-1270

Frontiers in Oncology ◽

10.3389/fonc.2020.596623 ◽

2021 ◽

Vol 10 ◽

Author(s):

Liping Luo ◽

Pingping Miao ◽

Yao Ming ◽

Jie Tao ◽

Hongchun Shen

Keyword(s):

Bladder Cancer ◽

Cell Lines ◽

Pearson Correlation ◽

Survival Rates ◽

Circular Rna ◽

Luciferase Assay ◽

Migration And Invasion ◽

Novel Target

BackgroundBladder cancer is one of the most common cancers all over the world. CircZFR is a circular RNA and has been implicated in tumor generation and invasion. However, the exact role of circZFR in the development of bladder cancer (BCa) remains unknown. This study aimed to investigate the function of circZFR in BCa, and further to probe into the association between circ-ZFR, miR-545/miR-1270 and WNT5A.MethodsThe expression of circZFR in BCa was quantified by qRT-PCR and was positively correlated with the prognosis of BCa patients. Next, the stable knockdown of circZFR BCa cell lines was established and the resulting capacities of proliferation, migration and invasion were measured. The association of circZFR with miR-1270/miR-545 was predicted by circinteractome prediction, and was confirmed by luciferase assay as well as RNA pull down assay. Furthermore, miRNA inhibitors, WNT5A overexpression and Pearson correlation analysis were used to examine the relationship between circZFR, miR-1270/miR-545 and WNT5A.ResultsThe expression of CircZFR was up-regulated both in BCa tissues and in BCa cell lines, and was positively correlated with patient survival rates. Blocking of circZFR’s expression by RNA inhibitors suppressed the proliferation, migration and invasion of BCa cells both in vitro and in vivo. On the other hand, overexpression of target miRNA supported that circZFR directly interact with miR-545 and miR-1270. Moreover, we demonstrated that circZFR promotes the progression of BCa by upregulating WNT5A’s expression via sponging miR-545 and miR-1270.ConclusionsCircZFR promotes the proliferation, migration and invasion of BCa cells by upregulating WNT5A signaling pathway via sponging miR-545 and miR-1270. These results provide new insights into the molecular mechanism of circZFR in BCa progression, and more important, a novel target for BCa clinical treatment.

Download Full-text