scholarly journals Blocking lncRNA-SNHG16 Sensitizes Gastric Cancer Cells to 5-Fu Through Targeting the miR-506-3p-PTBP1-Mediated Glucose Metabolism

2021 ◽  
Author(s):  
Yan Ding ◽  
Sujie Gao ◽  
Jiabin Zheng ◽  
Xuebo Chen
Keyword(s):  
Gastric Cancer ◽  
Glucose Metabolism ◽  
Molecular Mechanisms ◽  
Luciferase Assay ◽  
Rna Seq ◽  
Gastric Cancer Cells ◽  
Rna Immunoprecipitation ◽  
Low Glucose ◽  
Direct Target

Abstract Gastric cancer (GC) is one of the most human malignancies. The 5-fluorouracil (5-Fu) is a first-line anti-gastric cancer chemotherapeutic agent. However, a large number of GC patients developed 5-Fu resistance. Currently, the biological roles and molecular mechanisms of lncRNA-SNHG16 in 5-Fu resistant gastric cancer still remain elusive. Here we report SNHG16 as well as PTBP1 are positively associated with 5-Fu resistance of gastric cancer. SNHG16 and PTBP1 are significantly upregulated in gastric tumors and cell lines. Silencing SNHG16 or PTBP1 effectively sensitized GC cells to 5-Fu. Furthermore, the glucose metabolism was remarkedly elevated in 5-Fu resistant GC cells. Under low glucose supply, 5-Fu resistant cells displayed higher vulnerability than parental GC cells. Bioinformatical analysis and luciferase assay demonstrated that SNHG16 downregulated miR-506-3p by sponging it. We identified PTBP1 was a direct target of miR-506-3p in GC cells. RNA-seq results indicated PTBP1 positively regulated multiple glycolysis enzymes expressions, including GLUT1, HK2 and LDHA. Bioinformatics analysis illustrated the 3’UTRs of glycolysis enzymes contained multiple PTBP1 binding sites, which were further verified by RNA-pull down and RNA immunoprecipitation assays. Consequently, we demonstrated PTBP1 upregulated the mRNAs of glycolysis enzymes via promoting the mRNAs stabilities. Finally, in vivo xenograft experiments validated that blocking the SNHG16-mediated miR-506-3p-PTBP1 axis effectively sensitized xenograft tumors to 5-Fu treatments. Summarily, our study reports biological roles and molecular mechanisms underlying the lncRNA SNHG16-mediated 5-Fu resistance in GC through modulating the miR-506-3p-PTBP1-glycolysis axis, presenting a promising prospect in improvement of 5-Fu therapy for chemoresistant GC patients.

scholarly journals miR-26a/HOXC9 Dysregulation Promotes Metastasis and Stem Cell-Like Phenotype of Gastric Cancer

2018 ◽  
Vol 49 (4) ◽  
pp. 1659-1676 ◽  
Author(s):  
Xudong Peng ◽  
Qingjie Kang ◽  
Rui Wan ◽  
Ziwei Wang
Keyword(s):  
Gastric Cancer ◽  
Stem Cell ◽  
Molecular Mechanisms ◽  
Luciferase Reporter ◽  
Loss Of Function ◽  
Promoting Effect ◽  
In Vivo Experiments ◽  
Direct Target ◽  
Cancer Tissues

Background/Aims: Previous studies demonstrated that HOXC9 acts as an oncogene in several tumors. The aim of this study was to explore whether HOXC9 promotes gastric cancer (GC) progression and elucidate the underlying molecular mechanisms. Methods: HOXC9 expression in GC tissues and adjacent non-cancer tissues was detected by quantitative RT-PCR (qRT-PCR) and immunohistochemistry. The functional effects of HOXC9 on proliferation, metastasis and stem cell-like phenotype were evaluated by relevant experiments in GC cells. The effect of miR-26a on HOXC9 was investigated by gain- and loss-of-function assays and luciferase reporter assay. Nude mouse models were established to test the effect of miR-26a and HOXC9 on tumorigenesis and metastasis of GC cells in vivo. Results: Herein, we showed that HOXC9 was upregulated in GC tissues and associated with a poor prognosis. HOXC9 knockdown inhibited the metastasis and stem cell-like phenotype of GC cells without significant effects on cell proliferation. In addition, we identifed HOXC9 as a direct target of miR-26a. Restoration of miR-26a in GC cells downregulated HOXC9 and reversed its promoting effect on metastasis and self-renewal, whereas miR-26a silencing upregulated HOXC9. In vivo experiments showed that HOXC9 knockdown suppressed tumorigenesis and lung metastasis of GC cells in nude mice, and these effects were mimicked by restoration of miR-26a. Conclusion: The present study demonstrates that HOXC9 promotes the metastasis and stem cell-like phenotype of GC cells, and this phenomenon can be reversed by restoration of miR-26a.

scholarly journals Anti-Cancer Effects of Radix Angelica Sinensis (Danggui) and N-Butylidenephthalide on Gastric Cancer: Implications for REDD1 Activation and mTOR Inhibition

2018 ◽  
Vol 48 (6) ◽  
pp. 2231-2246 ◽  
Author(s):  
Kuan-Fu Liao ◽  
Tsung-Lang Chiu ◽  
Sung-Ying Huang ◽  
Teng-Fu Hsieh ◽  
Shu-Fang Chang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Survival Rate ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Gastric Cancer Cell ◽  
Angelica Sinensis ◽  
Rna Seq ◽  
Gastric Cancer Cells ◽  
Mtor Inhibition

Background/Aims: Radix Angelica Sinensis (danggui in Chinese) is widely used in traditional chinese medicine (TCM). N-butylidenephthalide (BP), a bioactive compound in danggui, is a potential antitumor agent for various cancer types. However, its clinical effect and mechanism in the treatment of gastric cancer remain undetermined. Methods: The in vivo protective effect of danggui in patients with gastric cancer were validated using data from Taiwan’s National Health Insurance Research Database (NHIRD). The genes induced by BP-treatment were analyzed by whole transcriptome RNA sequencing (RNA-seq) and validated by real-time PCR, western blot and siRNA transfection. The effect of BP on AGS cell migration and invasion was evaluated in transwell assays. The antitumor effects of BP were evaluated in vivo in an AGS xenograft animal model. Results: Danggui users were found to have an increased survival rate when compared with danggui nonusers (log-rank test p = 0.002) . The use of danggui highly associated with decreased mortality (the adjusted hazard ratio (HR) of danggui user was 0.72 [95 % CI, 0.57-0.92] (p = 0.009). The in vitro results showed that BP inhibited gastric cancer cell proliferation, and triggered cellular apoptosis depending on the activation of mitochondrial apoptotic pathway. Using RNA-seq analysis we found that REDD1 was the highest transcript induced by BP in gastric cancer cells. BP induce an increase of REDD1 expression that inhibits mTOR signaling, thus inhibiting gastric cancer growth. We used RNA interference to demonstrate that the knock-down of REDD1 attenuated the BP-induced mTORC1 activation and growth inhibition. BP suppressed the growth of AGS xenografts tumor in vivo. Conclusion: Danggui can prolong the survival rate of gastric cancer patients in Taiwan. BP caused gastric cancer cell death through the activation of mitochondria-intrinsic pathway and induced the REDD1 expression leading to mTOR signal pathway inhibition in gastric cancer cells. BP inhibited the in vivo growth of AGS xenograft tumors. These results may provide the basis for a new therapeutic approach toward the treatment of gastric cancer progression.

scholarly journals miR-125b Suppresses Proliferation and Invasion by Targeting MCL1 in Gastric Cancer

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Shihua Wu ◽  
Feng Liu ◽  
Liming Xie ◽  
Yaling Peng ◽  
Xiaoyuan Lv ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Clinical Stage ◽  
Gastric Cancer Cells ◽  
Gastric Cancer Progression

Understanding the molecular mechanisms underlying gastric cancer progression contributes to the development of novel targeted therapies. In this study, we found that the expression levels of miR-125b were strongly downregulated in gastric cancer and associated with clinical stage and the presence of lymph node metastases. Additionally, miR-125b could independently predict OS and DFS in gastric cancer. We further found that upregulation of miR-125b inhibited the proliferation and metastasis of gastric cancer cells in vitro and in vivo. miR-125b elicits these responses by directly targeting MCL1 (myeloid cell leukemia 1), which results in a marked reduction in MCL1 expression. Transfection of miR-125b sensitizes gastric cancer cells to 5-FU-induced apoptosis. By understanding the function and molecular mechanisms of miR-125b in gastric cancer, we may learn that miR-125b has the therapeutic potential to suppress gastric cancer progression and increase drug sensitivity to gastric cancer.

scholarly journals LncRNA FEZF1-AS1 Promotes Multi-Drug Resistance of Gastric Cancer Cells via Upregulating ATG5

2021 ◽  
Vol 9 ◽  
Author(s):  
Zhifu Gui ◽  
Zhenguo Zhao ◽  
Qi Sun ◽  
Guoyi Shao ◽  
Jianming Huang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Drug Resistance ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Underlying Mechanism ◽  
Multi Drug Resistance ◽  
Gastric Cancer Cells ◽  
Poor Overall Survival

Long non-coding RNAs (lncRNAs) play important roles in human cancers including gastric cancer (GC). Dysregulation of lncRNAs is involved in a variety of pathological activities associated with gastric cancer progression and chemo-resistance. However, the role and molecular mechanisms of FEZF1-AS1 in chemoresistance of GC remain unknown. In this study, we aimed to determine the role of FEZF1-AS1 in chemoresistance of GC. The level of FEZF1-AS1 in GC tissues and GC cell lines was assessed by qRT-PCR. Our results showed that the expression of FEZF1-AS1 was higher in gastric cancer tissues than in adjacent normal tissues. Multivariate analysis identified that high level of FEZF1-AS1 is an independent predictor for poor overall survival. Increased FEZF1-AS1 expression promoted gastric cancer cell proliferation in vitro. Additionally, FEZF1-AS1 was upregulated in chemo-resistant GC tissues. The regulatory effect of FEZF1-AS1 on multi-drug resistance (MDR) in GC cells and the underlying mechanism was investigated. It was found that increased FEZF1-AS1 expression promoted chemo-resistance of GC cells. Molecular interactions were determined by RNA immunoprecipitation (RIP) and the results showed that FEZF1-AS1 regulated chemo-resistance of GC cells through modulating autophagy by directly targeting ATG5. The proliferation and autophagy of GC cells promoted by overexpression of LncFEZF1-AS1 was suppressed when ATG5 was knocked down. Moreover, knockdown of FEZF1-AS1 inhibited tumor growth and increased 5-FU sensitivity in GC cells in vivo. Taken together, this study revealed that the FEZF1-AS1/ATG5 axis regulates MDR of GC cells via modulating autophagy.

scholarly journals MiR-122-5p suppresses the proliferation, migration, and invasion of gastric cancer cells by targeting LYN

2019 ◽  
Vol 52 (1) ◽  
pp. 49-57 ◽  
Author(s):  
Lei Meng ◽  
Zhangming Chen ◽  
Zhe Jiang ◽  
Ting Huang ◽  
Jie Hu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Biological Function ◽  
Malignant Tumors ◽  
Luciferase Assay ◽  
Migration And Invasion ◽  
Gastric Cancer Cells ◽  
Mortality And Morbidity ◽  
Qrt Pcr ◽  
The World ◽  
Direct Target

Abstract Gastric cancer (GC) is one of malignant tumors with high mortality and morbidity in the world. MicroRNA-122 (miR-122) acts as a tumor suppressor in a variety of cancers and has been found to be dominant in gastric adenocarcinoma. However, the specific biological function of miR-122-5p in GC is not completely clear. In this study, we found that miR-122-5p was low-expressed in GC tissues and cell lines by using qRT-PCR. Overexpression of miR-122-5p inhibited the proliferation, migration, and invasion of GC cells by using CCK-8 and transwell assays. On the contrary, downregulation of miR-122-5p promoted the proliferation, migration, and invasion of GC cells. In addition, we found that the expression of LYN, an Src family tyrosine kinase, was inversely correlated with miR-122-5p expression in GC tissues by using western blot analysis, immunohistochemistry, and qRT-PCR assays. Meanwhile, luciferase assay results indicated that LYN is a direct target of miR-122-5p in GC cells. Moreover, silencing LYN expression by its siRNA inhibited the proliferation, migration, and invasion of GC cells. Importantly, overexpression of LYN restored miR-122-5p-mediated inhibition of the proliferation, migration, and invasion of GC cells. Taken together, our results indicated miR-122-5p inhibited the proliferation, migration, and invasion by targeting LYN in GC.

scholarly journals The circBVES Acts as a Sponge of miR-145-5p to Promote Gastric Cancer Glycolysis and Progression Through Regulating HMGB3 Expression

2020 ◽  
Author(s):  
Lu Jin ◽  
Zhiwei He ◽  
Changhao Zhu ◽  
Guoliang Xiao ◽  
Xianjin Yang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Quantitative Polymerase Chain Reaction ◽  
Gastric Cancer Cells ◽  
Repressive Effect ◽  
Cancer Tissues

Abstract Background: CircRNA is a new type of non-coding RNA that has attracted much attention for involvement in the development and progression of various human diseases, especially cancer. The most reported role of circRNA in many tumors is ‘MiRNA sponge’. We aimed to investigate the role of circBVES in the proliferation and glycolysis of gastric cancer cells and its molecular mechanisms.Methods: In this study, higher CircBVES expression in gastric cancer tissues was detected by RNA sequencing. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to detect the expression of CircBVES in gastric cancer tissues, and the relationship between the expression of CircBVES and prognosis was further analyzed. Then, the effects of CircBVES on the growth and glycolysis of gastric cancer cells were investigated through in vitro and in vivo functional experiments. The interaction between CircBVES and miR-145-5p was detected by bioinformatics analysis, luciferase activity assay and RNA immunoprecipitation.Results: We found that the expression of CircBVES in gastric cancer tissues was evidently up-regulated, and its level was closely correlated with the prognosis of patients with gastric cancer. Inhibition of CircBVES decreased cell proliferation and glycolysis in vitro. Low expression of CircBVES inhibited tumor growth in vivo. Mechanism analysis showed that CircBVES may serve as a competitive endogenous RNA of miR-145-5p to reduce the expression of miR-145-5p in gastric cancer cells, and relieve the repressive effect of miR-145-5p on target genes HMGB3 and cycle-related proteins CCNE1 and CDK2.Conclusions: Our results suggest that CircAGFG1 may promote the progress of gastric cancer through the CircBVES / miR-145-5p / HMGB3 axis, providing a new target for the treatment of gastric cancer cells.

scholarly journals Multicellular Human Gastric Cancer Spheroids Mimic the Glycosylation Phenotype of Gastric Carcinomas

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2815 ◽  
Author(s):  
Meritxell Balmaña ◽  
Stefan Mereiter ◽  
Francisca Diniz ◽  
Tália Feijão ◽  
Cristina Barrias ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Molecular Mechanisms ◽  
3D Cell Culture ◽  
Automated Image Analysis ◽  
Human Gastric Cancer ◽  
Gastric Cancer Cells ◽  
Model Cell ◽  
Cancer Spheroids ◽  
The Impact

Cellular glycosylation plays a pivotal role in several molecular mechanisms controlling cell–cell recognition, communication, and adhesion. Thus, aberrant glycosylation has a major impact on the acquisition of malignant features in the tumor progression of patients. To mimic these in vivo features, an innovative high-throughput 3D spheroid culture methodology has been developed for gastric cancer cells. The assessment of cancer cell spheroids’ physical characteristics, such as size, morphology and solidity, as well as the impact of glycosylation inhibitors on spheroid formation was performed applying automated image analysis. A detailed evaluation of key glycans and glycoproteins displayed by the gastric cancer spheroids and their counterpart cells cultured under conventional 2D conditions was performed. Our results show that, by applying 3D cell culture approaches, the model cell lines represented the differentiation features observed in the original tumors and the cellular glycocalix underwent striking changes, displaying increased expression of cancer-associated glycan antigens and mucin MUC1, ultimately better simulating the glycosylation phenotype of the gastric tumor.

scholarly journals The circular RNA circDLG1 promotes gastric cancer progression and anti-PD-1 resistance through the regulation of CXCL12 by sponging miR-141-3p

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Dong-Liang Chen ◽  
Hui Sheng ◽  
Dong-Sheng Zhang ◽  
Ying Jin ◽  
Bai-Tian Zhao ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Progression ◽  
Immune Evasion ◽  
Molecular Mechanisms ◽  
Circular Rnas ◽  
Gastric Cancer Cells ◽  
Cancer Tissues ◽  
Gastric Cancer Progression

Abstract Background Dysregulation of circular RNAs (circRNAs) plays an important role in the development of gastric cancer; thus, revealing the biological and molecular mechanisms of abnormally expressed circRNAs is critical for identifying novel therapeutic targets in gastric cancer. Methods A circRNA microarray was performed to identify differentially expressed circRNAs between primary and distant metastatic tissues and between gastric cancer tissues sensitive or resistant to anti-programmed cell death 1 (PD-1) therapy. The expression of circRNA discs large homolog 1 (DLG1) was determined in a larger cohort of primary and distant metastatic gastric cancer tissues. The role of circDLG1 in gastric cancer progression was evaluated both in vivo and in vitro, and the effect of circDLG1 on the antitumor activity of anti-PD-1 was evaluated in vivo. The interaction between circDLG1 and miR-141-3p was assessed by RNA immunoprecipitation and luciferase assays. Results circDLG1 was significantly upregulated in distant metastatic lesions and gastric cancer tissues resistant to anti-PD-1 therapy and was associated with an aggressive tumor phenotype and adverse prognosis in gastric cancer patients treated with anti-PD-1 therapy. Ectopic circDLG1 expression promoted the proliferation, migration, invasion, and immune evasion of gastric cancer cells. Mechanistically, circDLG1 interacted with miR-141-3p and acted as a miRNA sponge to increase the expression of CXCL12, which promoted gastric cancer progression and resistance to anti-PD-1-based therapy. Conclusions Overall, our findings demonstrate how circDLG1 promotes gastric cancer cell proliferation, migration, invasion and immune evasion and provide a new perspective on the role of circRNAs during gastric cancer progression.

scholarly journals LncRNA AC245100.4 affects the tumorigenesis of prostate cancer via regulating the STAT3/NR4A3 axis

2020 ◽  
Author(s):  
Chi Liu ◽  
Ping Lin ◽  
Jiabin Zhao ◽  
Hui Xie ◽  
Tianhu Zheng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Rna Seq ◽  
Rna Immunoprecipitation ◽  
Cancer Tissues ◽  
Promising Avenue

Abstract Background Prostate cancer (PCa) is the second most common cancer and the fifth leading cause of cancer deaths among men globally. However, the molecular mechanisms leading to the progression have not been fully elucidated. Methods The expression and location of AC245100.4 were examined by RT-qPCR and nuclear-cytoplasmic separation assay. RNA-seq analysis was performed to identify the downstream of AC245100.4. RNA immunoprecipitation was performed to identify the proteins those bind to AC245100.4. Western blotting was performed to quantify the expression of proteins. Finally, a series of gain- or loss-functional assays were done to prove the precise role of AC245100.4 and NR4A3 in PCa. Results We identify a critical lncRNA AC245100.4, which is significantly up-regulated in prostate cancer tissues and cells. Knockdown of AC21500.4 can significantly inhibit prostate cancer progression in vitro and in vivo. Further RNA-seq analysis shows that NR4A3 may be the potential target of AC245100.4. Mechanistically, AC245100.4 de-regulates NR4A3 transcriptionally via increasing p-STAT3, which is a transcriptional repressor of NR4A3. Conclusion Our results demonstrated that AC245100.4 was a critically oncogenic lncRNA in PCa via inhibiting NR4A3 and paved a promising avenue to combat PCa progression by targeting AC245100.4 or NR4A3.

scholarly journals PLXDC2 Enhances Invadopodium Formation to Promote Invasion and Metastasis of Gastric Cancer Cells via Iteracting with PTP1B

2021 ◽  
Author(s):  
Bin Wu ◽  
Yan-xia Wang ◽  
Jun-jie Wang ◽  
Dong-fang Xiang ◽  
Meng-si Zhang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Cox Regression ◽  
Tyrosine Phosphatase ◽  
Invasion And Metastasis ◽  
Gastric Cancer Cells ◽  
Cox Regression Analysis

Abstract Background: Plexin-domain containing 2 (PLXDC2) has been reported as an oncoprotein in several human malignancies. However, its expression and roles in gastric cancer remain largely unclear. Methods: The expression of PLXDC2 in 170 gastric cancer specimens was measured by using immunohistochemical staining and its clinical relevance was statistically analyzed. Matrigel-transwell invasion assays and mouse intraperitoneal metastasis models with PLXDC2-silencing and -overexpressing gastric cells were performed to explore the biological functions of PLXDC2 in gastric cancer cells. RNA-Seq, immunofluorescence and Co-IP analyses were used to investigate the potential molecular mechanisms of PLXDC2 action in gastric cancer. Results: PLXDC2 was highly expressed in gastric cancer tissues, and the expression levels were positively correlated with clinicopathological features, but negatively with the patients’ outcome. Cox regression analysis identified PLXDC2 as an independent prognostic indicator for the patients. Knockdown of PLXDC2 markedly suppressed the in vitro invasion and in vivo metastasis of gastric cancer cells, while overexpression of PLXDC2 resulted in opposite effects. Mechanistically, PLXDC2 inhibited dephosphorylation of phosphorylated Cortactin by physically interacting with PTP1B, an important tyrosine phosphatase, thereby promoting the formation of invadopodium. Conclusions: PLXDC2 contributes to the invasion and metastasis of gastric cancer by inhibiting PTP1B to facilitate the invadopodium formation, and may serve as a potential prognostic biomarker and a therapeutic target for this disease.

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