Long noncoding RNA LINC00941 promotes pancreatic cancer progression by competitively binding miR-335-5p to regulate ROCK1-mediated LIMK1/Cofilin-1 signaling

AbstractAn accumulation of evidence indicates that long noncoding RNAs are involved in the tumorigenesis and progression of pancreatic cancer (PC). In this study, we investigated the functions and molecular mechanism of action of LINC00941 in PC. Quantitative PCR was used to examine the expression of LINC00941 and miR-335-5p in PC tissues and cell lines, and to investigate the correlation between LINC00941 expression and clinicopathological features. Plasmid vectors or lentiviruses were used to manipulate the expression of LINC00941, miR-335-5p, and ROCK1 in PC cell lines. Gain or loss-of-function assays and mechanistic assays were employed to verify the roles of LINC00941, miR-335-5p, and ROCK1 in PC cell growth and metastasis, both in vivo and in vitro. LINC00941 and ROCK1 were found to be highly expressed in PC, while miR-335-5p exhibited low expression. High LINC00941 expression was strongly associated with larger tumor size, lymph node metastasis, and poor prognosis. Functional experiments revealed that LINC00941 silencing significantly suppressed PC cell growth, metastasis and epithelial–mesenchymal transition. LINC00941 functioned as a molecular sponge for miR-335-5p, and a competitive endogenous RNA (ceRNA) for ROCK1, promoting ROCK1 upregulation, and LIMK1/Cofilin-1 pathway activation. Our observations lead us to conclude that LINC00941 functions as an oncogene in PC progression, behaving as a ceRNA for miR-335-5p binding. LINC00941 may therefore have potential utility as a diagnostic and treatment target in this disease.

Download Full-text

Orai3 Regulates Pancreatic Cancer Metastasis by Encoding a Functional Store Operated Calcium Entry Channel

10.20944/preprints202110.0400.v1 ◽

2021 ◽

Author(s):

Samriddhi Arora ◽

Jyoti Tanwar ◽

Nutan Sharma ◽

Suman Saurav ◽

Rajender K. Motiani

Keyword(s):

Pancreatic Cancer ◽

Survival Time ◽

Cell Lines ◽

Cancer Progression ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Critical Role ◽

Mesenchymal Transition

Pancreatic cancer (PC) is one of the most lethal forms of cancers with 5-year mean survival rate of less than 10%. Most of the PC associated deaths are due to metastasis to secondary sites. Calcium (Ca2+) signaling plays a critical role in regulating hallmarks of cancer progression including cell proliferation, migration and apoptotic resistance. Store operated Ca2+ entry (SOCE) mediated by Orai1/2/3 channels is a highly regulated and ubiquitous pathway responsible for Ca2+ influx into non-excitable cells. In this study, we performed extensive bioinformatic analysis of publicly available datasets and observed that Orai3 expression is inversely associated with the mean survival time of PC patients. Orai3 expression analysis in a battery of PC cell lines corroborated its differential expression profile. We then carried out thorough Ca2+ imaging experiments in 6 PC cell lines and found that Orai3 forms a functional SOCE in PC cells. Our in vitro functional assays show that Orai3 regulates PC cell cycle progression, apoptosis and migration. Most importantly, our in vivo xenograft studies demonstrate a critical role of Orai3 in PC tumor growth and secondary metastasis. Mechanistically, Orai3 controls G1 phase progression, matrix metalloproteinase expression and epithelial-mesenchymal transition in PC cells. Taken together, this study for the first time reports that Orai3 drives aggressive phenotypes of PC cells i.e. migration in vitro and metastasis in vivo. Considering that Orai3 expression is inversely associated with the PC patients survival time, it appears to be a highly attractive therapeutic target.

Download Full-text

MicroRNA-1252-5p, regulated by Myb, inhibits invasion and epithelial-mesenchymal transition of pancreatic cancer cells by targeting NEDD9

10.21203/rs.3.rs-91605/v1 ◽

2020 ◽

Author(s):

Yuzheng Xue ◽

Tielong Wu ◽

Yingyue Sheng ◽

Yao zhong ◽

Benshun Hu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Lines ◽

Epithelial Mesenchymal Transition ◽

Luciferase Reporter ◽

Mechanistic Study ◽

Loss Of Function ◽

Mesenchymal Transition ◽

Pancreatic Cancer Cells

Abstract Background: MicroRNAs (miRNAs) are known to be involved in the development and progression of pancreatic cancer (PAC). The expression level and role of miR-1252-5p in PAC remain unclear. Methods: qRT-PCR and in situ hybridization were used to detect miR-1252-5p expression in PAC cells and tissues. Associations between miR-1252-5p expression and clinical characteristics or overall survival (OS) were assessed based on 102 patients with PAC who underwent surgical resection. Gain and loss of function of miR-1252-5p was studied in the PAC cell lines, Panc-1 and BxPC 3 in vitro and in vivo. The direct targets of miR-1252-5p were analyzed using public databases and a dual-luciferase reporter assay.Results: The expression levels of miR-1252-5p are downregulated in PAC cell lines and tissue samples compared to control, and its expression is negatively associated with adverse clinical features and poor prognosis. In vitro and in vivo experiments show that miR-1252-5p overexpression inhibits the proliferation, migration, invasion and epithelial-mesenchymal transition of PAC cells, whereas miR-1252-5p knockdown enhances these biological behaviors. In addition, miR-1252-5p negatively regulates neural precursor cell expressed, developmentally downregulated 9 (NEDD9) by directly binding its 3'-UTR. NEDD9 restoration at least partially abolishes this effect of miR-1252-5p in PAC cells. Further mechanistic study revealed that the SRC/STAT3 pathway is involved in miR-1252-5p/NEDD9 mediation of biological behaviors in PAC. We also verified that Myb inhibited miR-1252-5p by directly binding at its promoter.Conclusion: MiR-1252-5p may act as a tumor-suppressing miRNA in PAC and may be a potential therapeutic target for PAC patients.

Download Full-text

LncRNA SNHG4 promotes the proliferation, migration, invasiveness, and epithelial–mesenchymal transition of lung cancer cells by regulating miR-98-5p

Biochemistry and Cell Biology ◽

10.1139/bcb-2019-0065 ◽

2019 ◽

Vol 97 (6) ◽

pp. 767-776 ◽

Cited By ~ 7

Author(s):

Yufu Tang ◽

Lijian Wu ◽

Mingjing Zhao ◽

Guangdan Zhao ◽

Shitao Mao ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Noncoding Rna ◽

Epithelial Mesenchymal Transition ◽

Lung Cancer Cells ◽

Mesenchymal Transition ◽

Gene 4

Long noncoding RNA small nucleolar RNA host gene 4 (SNHG4) is usually up-regulated in cancer and regulates the malignant behavior of cancer cells. However, its role in lung cancer remains elusive. In this study, we silenced the expression of SNHG4 in NCI-H1437 and SK-MES-1, two representative non-small-cell lung cancer cell lines, by transfecting them with siRNA (small interfering RNA) that specifically targets SNHG4. We observed significantly inhibited cell proliferation in vitro and reduced tumor growth in vivo after SNHG4 silencing. SNHG4 knockdown also led to cell cycle arrest at the G1 phase, accompanied with down-regulation of cyclin-dependent kinases CDK4 and CDK6. The migration and invasiveness of these two cell lines were remarkably inhibited after SNHG4 silencing. Moreover, our study revealed that the epithelial–mesenchymal transition (EMT) of lung cancer cells was suppressed by SNHG4 silencing, as evidenced by up-regulated E-cadherin and down-regulated SALL4, Twist, and vimentin. In addition, we found that SNHG4 silencing induced up-regulation of miR-98-5p. MiR-98-5p inhibition abrogated the effect of SNHG4 silencing on proliferation and invasion of lung cancer cells. In conclusion, our findings demonstrate that SNHG4 is required by lung cancer cells to maintain malignant phenotype. SNHG4 probably exerts its pro-survival and pro-metastatic effects by sponging anti-tumor miR-98-5p.

Download Full-text

miR551b Regulates Colorectal Cancer Progression by Targeting the ZEB1 Signaling Axis

Cancers ◽

10.3390/cancers11050735 ◽

2019 ◽

Vol 11 (5) ◽

pp. 735 ◽

Cited By ~ 2

Author(s):

Kwang Seock Kim ◽

Dongjun Jeong ◽

Ita Novita Sari ◽

Yoseph Toni Wijaya ◽

Nayoung Jun ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Lines ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

Ectopic Expression ◽

Xenograft Model ◽

Mesenchymal Transition ◽

Normal Tissues

Our current understanding of the role of microRNA 551b (miR551b) in the progression of colorectal cancer (CRC) remains limited. Here, studies using both ectopic expression of miR551b and miR551b mimics revealed that miR551b exerts a tumor suppressive effect in CRC cells. Specifically, miR551b was significantly downregulated in both patient-derived CRC tissues and CRC cell lines compared to normal tissues and non-cancer cell lines. Also, miR551b significantly inhibited the motility of CRC cells in vitro, including migration, invasion, and wound healing rates, but did not affect cell proliferation. Mechanistically, miR551b targets and inhibits the expression of ZEB1 (Zinc finger E-box-binding homeobox 1), resulting in the dysregulation of EMT (epithelial-mesenchymal transition) signatures. More importantly, miR551b overexpression was found to reduce the tumor size in a xenograft model of CRC cells in vivo. Furthermore, bioinformatic analyses showed that miR551b expression levels were markedly downregulated in the advanced-stage CRC tissues compared to normal tissues, and ZEB1 was associated with the disease progression in CRC patients. Our findings indicated that miR551b could serve as a potential diagnostic biomarker and could be utilized to improve the therapeutic outcomes of CRC patients.

Download Full-text

SNHG5 inhibits the progression of EMT through the ubiquitin-degradation of MTA2 in oesophageal cancer

Carcinogenesis ◽

10.1093/carcin/bgaa110 ◽

2020 ◽

Author(s):

Sisi Wei ◽

Shiping Sun ◽

Xinliang Zhou ◽

Cong Zhang ◽

Xiaoya Li ◽

...

Keyword(s):

Cell Lines ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

Survival Rates ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Underlying Mechanisms ◽

And Function

Abstract A substantial fraction of transcripts are known as long noncoding RNAs (lncRNAs), and these transcripts play pivotal roles in the development of cancer. However, little information has been published regarding the functions of lncRNAs in oesophageal squamous cell carcinoma (ESCC) and the underlying mechanisms. In our previous studies, we demonstrated that small nucleolar RNA host gene 5 (SNHG5), a known lncRNA, is dysregulated in gastric cancer (GC). In this study, we explored the expression and function of SNHG5 in development of ESCC. SNHG5 was found to be downregulated in human ESCC tissues and cell lines, and this downregulation was associated with cancer progression, clinical outcomes and survival rates of ESCC patients. Furthermore, we also found that overexpression of SNHG5 significantly inhibited the proliferation, migration and invasion of ESCC cells in vivo and in vitro. Notably, we found that metastasis-associated protein 2 (MTA2) was pulled down by SNHG5 in ESCC cells using RNA pulldown assay. We also found that SNHG5 reversed the epithelial–mesenchymal transition by interacting with MTA2. In addition, overexpression of SNHG5 downregulated the transcription of MTA2 and caused its ubiquitin-mediated degradation. Thus, overexpression of MTA2 partially abrogated the effect of SNHG5 in ESCC cell lines. Furthermore, we found that MTA2 mRNA expression was significantly elevated in ESCC specimens, and a negative correlation between SNHG5 and MTA2 expression was detected. Overall, this study demonstrated, for the first time, that SNHG5-regulated MTA2 functions as an important player in the progression of ESCC and provide a new potential therapeutic strategy for ESCC.

Download Full-text

The YAP1–NMU Axis Is Associated with Pancreatic Cancer Progression and Poor Outcome: Identification of a Novel Diagnostic Biomarker and Therapeutic Target

Cancers ◽

10.3390/cancers11101477 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1477 ◽

Cited By ~ 4

Author(s):

Yoo ◽

Lee ◽

Jun ◽

Noh ◽

Lee ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Progression ◽

Target Genes ◽

Epithelial Mesenchymal Transition ◽

The Cancer Genome Atlas ◽

Mesenchymal Transition ◽

Tumor Group ◽

Cancer Genome Atlas

Yes-associated protein (YAP)-1 is highly upregulated in pancreatic cancer and associated with tumor progression. However, little is known about the role of YAP1 and related genes in pancreatic cancer. Here, we identified target genes regulated by YAP1 and explored their role in pancreatic cancer progression and the related clinical implications. Analysis of different pancreatic cancer databases showed that Neuromedin U (NMU) expression was positively correlated with YAP1 expression in the tumor group. The Cancer Genome Atlas data indicated that high YAP1 and NMU expression levels were associated with poor mean and overall survival. YAP1 overexpression induced NMU expression and transcription and promoted cell motility in vitro and tumor metastasis in vivo via upregulation of epithelial–mesenchymal transition (EMT), whereas specific inhibition of NMU in cells stably expressing YAP1 had the opposite effect in vitro and in vivo. To define this functional association, we identified a transcriptional enhanced associate domain (TEAD) binding site in the NMU promoter and demonstrated that YAP1–TEAD binding upstream of the NMU gene regulated its transcription. These results indicate that the identified positive correlation between YAP1 and NMU is a potential novel drug target and biomarker in metastatic pancreatic cancer.

Download Full-text

LncRNA ST7-AS1, by regulating miR-181b-5p/KPNA4 axis, promotes the malignancy of lung adenocarcinoma

Cancer Cell International ◽

10.1186/s12935-020-01652-7 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Rong-Hang Hu ◽

Zi-Teng Zhang ◽

Hai-Xiang Wei ◽

Lu Ning ◽

Jiang-Shan Ai ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Noncoding Rna ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Luciferase Assay ◽

Migration And Invasion ◽

Loss Of Function ◽

Mesenchymal Transition

Abstract Background Growing evidence suggests that suppressor of tumorigenicity 7 antisense RNA 1 (ST7-AS1) is an oncogenic long noncoding RNA (lncRNA). However, little is known on its clinical significance, biological functions, or molecular mechanisms in lung adenocarcinoma (LUAD). Methods The expression of ST7-AS1 and miR-181b-5p were examined by qRT-PCR. The correlations between ST7-AS1 level and different clinicopathological features were analysed. In vitro, LUAD cells were examined for cell viability, migration and invasion by MTT, wound healing and Transwell assay, respectively. Epithelial-mesenchymal transition (EMT) biomarkers were detected by Western blot. The regulations between ST7-AS1, miR-181b-5p, and KPNA4 were examined by luciferase assay, RNA immunoprecipitation, RNA pulldown. Both gain- and loss-of-function strategies were used to assess the importance of different signalling molecules in malignant phenotypes of LUAD cells. The in vivo effect was analysed using the xenograft and the experimental metastasis mouse models. Results ST7-AS1 was upregulated in LUAD tissues or cell lines, correlated with tumours of positive lymph node metastasis or higher TNM stages, and associated with shorter overall survival of LUAD patients. ST7-AS1 essentially maintained the viability, migration, invasion, and EMT of LUAD cells. The oncogenic activities of ST7-AS1 were accomplished by sponging miR-181b-5p and releasing the suppression of the latter on KPNA4. In LUAD tissues, ST7-AS1 level positively correlated with that of KPNA4 and negatively with miR-181b-5p level. In vivo, targeting ST7-AS1 significantly inhibited xenograft growth and metastasis. Conclusions ST7-AS1, by regulating miR-181b-5p/KPNA4 axis, promotes the malignancy of LUAD cells. Targeting ST7-AS1 and KPNA4 or up-regulating miR-181b-5p, therefore, may benefit the treatment of LUAD.

Download Full-text

Silencing of circRNA circ_0001666 Represses EMT in Pancreatic Cancer Through Upregulating miR-1251 and Downregulating SOX4

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.684866 ◽

2021 ◽

Vol 8 ◽

Author(s):

Rundong Zhang ◽

Wanli Zhu ◽

Chenchao Ma ◽

Kaixing Ai

Keyword(s):

Pancreatic Cancer ◽

Cell Invasion ◽

Epithelial Mesenchymal Transition ◽

Tumor Development ◽

Circular Rnas ◽

Loss Of Function ◽

Survival Times ◽

Mesenchymal Transition

BackgroundPancreatic cancer (PC) is an aggressive malignancy and has a poor prognosis. Although emerging research has revealed that circular RNAs (circRNAs) are crucial modulators that control tumor development and metastasis, their functional involvement in PC has not been well characterized. Here, we examined whether and how circRNA circ_0001666 governs epithelial-mesenchymal transition (EMT) in PC.MethodsWe investigated the effects of circ_0001666 on EMT and PC cell invasion by gain- and loss-of-function assays. We also explored the mechanisms underlying the functions of circ_0001666 in PC cells.ResultsWe found that circ_0001666 is highly expressed in PC tissues and PC cell lines. Patients with high circ_0001666 expression had shorter survival times. In vitro and in vivo experiments have demonstrated that upregulation of circ_0001666 facilitates PC cell proliferation, EMT and invasiveness, whereas knockdown of circ_0001666 exhibits opposite functions. Moreover, circ_0001666 is able to bind to miR-1251, thus increasing the expression of SOX4, which is a direct downstream effector of miR-1251. The oncogenic effects of circ_0001666 on EMT and PC cell invasion were rescued by miR-1251 overexpression.ConclusionsThese results suggested that circ_0001666 acts as an oncogenic circRNA to promote EMT and invasion of PC cells through sponging miR-1251, and indicated that circ_0001666 could be explored as a potential therapeutic target for PC.

Download Full-text

CircRNA circ_0092314 Induces Epithelial-Mesenchymal Transition of Pancreatic Cancer Cells via Elevating the Expression of S100P by Sponging miR-671

Frontiers in Oncology ◽

10.3389/fonc.2021.675442 ◽

2021 ◽

Vol 11 ◽

Author(s):

Qian Shen ◽

Gang Zheng ◽

Yi Zhou ◽

Jin Tong ◽

Sanpeng Xu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

Circular Rnas ◽

Mesenchymal Transition ◽

Downstream Target ◽

Normal Tissues ◽

Pancreatic Cancer Cells

BackgroundCircular RNAs (circRNAs) is a novel class of non-coding RNAs that regulate gene expression during cancer progression. Circ_0092314 is a newly discovered circRNA that was upregulated in pancreatic cancer (PAAD) tissues. However, the detailed functions and underlying mechanisms of circ_0092314 in PAAD cells remain unclear.MethodsWe first determined the expression of circ_0092314 in PAAD and normal tissues and further investigated the functional roles of circ_0092314 in regulating epithelial-mesenchymal transition (EMT) of PAAD cells. We also assessed the regulatory action of circ_0092314 on the microRNA-671 (miR-671) and its target S100P.ResultsCirc_0092314 was markedly upregulated in PAAD tissues and cells, and its overexpression was closely correlated with worse prognosis of PAAD patients. Functionally, circ_0092314 promotes proliferation, invasion and EMT in vitro and tumor growth in vivo. Mechanistically, we demonstrated that circ_0092314 directly binds to miR-671 and relieve its suppression of the downstream target S100P, which induces EMT and activates the AKT signaling pathway. The tumor-promoting effects caused by overexpression of circ_0092314 could be revered by re-expression of miR-671 in PAAD cells.ConclusionsOverall, our study demonstrates that circ_0092314 exerts critical roles in promoting the EMT features of PAAD cells, and provides insight into how elevated expression of circ_0092314 might influence PAAD progression.

Download Full-text

The role of long noncoding RNA AL161431.1 in the development and progression of pancreatic cancer

10.21203/rs.3.rs-51229/v1 ◽

2020 ◽

Author(s):

Gang Ma ◽

Guichen Li ◽

Wufeng Fan ◽

Yuanhong Xu ◽

Shaowei Song ◽

...

Keyword(s):

Pancreatic Cancer ◽

Noncoding Rna ◽

Epithelial Mesenchymal Transition ◽

Bioinformatic Analysis ◽

Clinical Samples ◽

Mesenchymal Transition ◽

Cancer Cell Death

Abstract Background: Pancreatic cancer is known for its notorious fast progression and poor prognosis. Various long noncoding RNAs (lncRNAs) have been shown to be involved in the pathogenesis processes of pancreatic cancer.Methods: We first identified lncRNA AL161431.1 through bioinformatic analysis. Then, we explored the role of lncRNA AL161431.1 in the development and progression of pancreatic cancer by in vitro and in vivo experiments, including qRT-PCR, Western blot, immunofluorescence and immunohistochemistry assays, and flow cytometry, in BxPC-3 and SW1990 cells, as well as clinical samples. Results: We found that lncRNA AL161431.1 was highly expressed in patients with pancreatic cancer. Knock down of lncRNA AL161431.1 led to increased cancer cell death and cell cycle arrest. Xenograft growth of SW1990 cells with stable knockdown of lncRNA AL161431.1 in mice was significantly slower than that of SW1990 cells with scrambled control shRNA. Finally, we showed the involvement of lncRNA AL161431.1 in pancreatic cancer was related to its promotion of the epithelial mesenchymal transition pathway.Conclusions: LncRNA AL161431.1 is involved in the progression of pancreatic cancer through its promotion of the epithelial mesenchymal transition pathway.

Download Full-text