scholarly journals Antagonistic Roles of the Tumor Suppressor miR-210-3p and Oncomucin MUC4 Forming a Negative Feedback Loop in Pancreatic Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6197
Author(s):  
Nihad Boukrout ◽  
Mouloud Souidi ◽  
Fatima Lahdaoui ◽  
Belinda Duchêne ◽  
Bernadette Neve ◽  
...  

Background: Pancreatic adenocarcinoma (PDAC) is a deadly cancer with an extremely poor prognosis. MUC4 membrane-bound mucin is neoexpressed in early pancreatic neoplastic lesions and is associated with PDAC progression and chemoresistance. In cancers, microRNAs (miRNAs, small noncoding RNAs) are crucial regulators of carcinogenesis, chemotherapy response and even metastatic processes. In this study, we aimed at identifying and characterizing miRNAs activated downstream of MUC4-associated signaling in pancreatic adenocarcinoma. MiRnome analysis comparing MUC4-KD versus Mock cancer cells showed that MUC4 inhibition impaired miR-210-3p expression. Therefore, we aimed to better understand the miR-210-3p biological roles. Methods: miR-210-3p expression level was analyzed by RT-qPCR in PDAC-derived cell lines (PANC89 Mock and MUC4-KD, PANC-1 and MiaPACA-2), as well as in mice and patients tissues. The MUC4-miR-210-3p regulation was investigated using luciferase reporter construct and chromatin immunoprecipitation experiments. Stable cell lines expressing miR-210-3p or anti-miR-210-3p were established using CRISPR/Cas9 technology or lentiviral transduction. We evaluated the biological activity of miR-210-3p in vitro by measuring cell proliferation and migration and in vivo using a model of subcutaneous xenograft. Results: miR-210-3p expression is correlated with MUC4 expression in PDAC-derived cells and human samples, and in pancreatic PanIN lesions of Pdx1-Cre; LstopL-KrasG12D mice. MUC4 enhances miR-210-3p expression levels via alteration of the NF-κB signaling pathway. Chromatin immunoprecipitation experiments showed p50 NF-κB subunit binding on miR-210-3p promoter regions. We established a reciprocal regulation since miR-210-3p repressed MUC4 expression via its 3′-UTR. MiR-210-3p transient transfection of PANC89, PANC-1 and MiaPACA-2 cells led to a decrease in cell proliferation and migration. These biological effects were validated in cells overexpressing or knocked-down for miR-210-3p. Finally, we showed that miR-210-3p inhibits pancreatic tumor growth and proliferation in vivo. Conclusion: We identified a MUC4-miR-210-3p negative feedback loop in early-onset PDAC, but also revealed new functions of miR-210-3p in both in vitro and in vivo proliferation and migration of pancreatic cancer cells, suggesting a complex balance between MUC4 pro-oncogenic roles and miR-210-3p anti-tumoral effects.

2021 ◽  
Vol 30 ◽  
pp. 096368972110255
Author(s):  
Qing Wang ◽  
Kai Li ◽  
Xiaoliang Li

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Increasing evidence suggests that long non-coding RNAs (lncRNAs) function in the tumorigenesis of NSCLC. LINC00958, a newly identified lncRNA, has been reported to be closely linked to tumorigenesis in several cancers. However, its specific role in NSCLC remains unclear. In this study, we determined the expression of LINC00958 in NSCLC by RT-qPCR analysis and evaluated cell proliferation and migration by CCK-8 and transwell assays, respectively. We established a xenograft tumor model to examine the effect of LINC00958 on tumor growth in vivo. Luciferase reporter assays were performed to determine the interaction between LINC00958 and miR-204-3p and the interaction between miR-204-3p and KIF2A. We found that LINC00958 was up-regulated in NSCLC tissues and cell lines. Down-regulation of LINC00958 inhibited cell proliferation and migration in vitro and suppressed tumor growth in vivo. Besides, miR-204-3p was identified as a target of LINC00958 and miR-204-3p inhibitor could reverse the inhibitory effect of LINC00958 knockdown on proliferation and migration of NSCLC cells. We also validated that KIF2A, a direct target of miR-204-3p, was responsible for the biological role of LINC00958. KIF2A antagonized the effect of miR-204-3p on NSCLC cell proliferation and migration and was regulated by LINC00958/miR-204-3p. Taken together, these data indicate that the LINC00958/miR-204-3p/KIF2A axis is critical for NSCLC progression, which might provide a potential therapeutic target of NSCLC.


Author(s):  
Qinhua Liu ◽  
Ruonan Ran ◽  
Zhengsheng Wu ◽  
Xiaodan Li ◽  
Qingshu Zeng ◽  
...  

The present study was directed toward laying new findings for Extranodal natural killer/T-cell lymphoma (ENKL)-oriented therapy with a focus on long non-coding RNA (lncRNA)–microRNAs (miRNAs)–mRNA interaction. The expression and function of XIST (X-inactive specific transcript) were analyzed both in vivo and in vitro. The online database of lncRNA-miRNA interaction was used to screen the target of XIST, and miR-497 was selected. Next, the predicted binding between XIST and miR-497, and the dynamic effect of XIST and miR-497 on downstream Bcl-w was evaluated. We found that XIST dramatically increased in the blood of ENKL patients and cell lines. XIST knockdown suppressed the cell proliferation and migration in vivo and in vitro. Herein, we confirmed the negative interaction between XIST and miR-497. Moreover, XIST knockdown reduced the protein levels of Bcl-w, a downstream target of miR-497. XIST sponges miR-497 to promote Bcl-w expression, and finally modulating ENKL cell proliferation and migration. To be interested, inhibition of Bcl-w by ABT737 can overcome the high expression of XIST, and suppressed the ENKL proliferation and migration by inducing apoptosis. This study provided a novel experimental basis for ENKL-oriented therapy with a focus on the lncRNA–miRNA–mRNA interaction.


2017 ◽  
Vol 42 (4) ◽  
pp. 1670-1683 ◽  
Author(s):  
Yiran Si ◽  
Haiyang Zhang ◽  
Tao Ning ◽  
Ming Bai ◽  
Yi Wang ◽  
...  

Background/Aims: Abnormal expression of HGF is found in various cancers and correlates with tumor proliferation, metastasis and angiogenesis. However, the regulatory mechanism of the HGF-VEGF axis remains unclear. Methods: The expression characteristic of HGF in human gastric cancer tissues was shown by an immunohistochemistry assay, and the expression levels of target protein were detected by Western blot. The relative levels of miR-26a/b and target mRNA were examined by qRT-PCR. We used bioinformatics tools to search for miRNAs that can potentially target HGF. A luciferase assay was used to confirm direct targeting. Furthermore, the functions of miR-26a/b and HGF were evaluated by cell proliferation and migration assays in vitro and by the mouse xenograft tumor model in vivo. Results: We found that the HGF protein was clearly increased while miR-26a/b were dramatically down-regulated in gastric cancer. miR-26a/b directly bind to the 3’-UTR of HGF mRNA at specific targeting sites. We demonstrated that the repression of the HGF-VEGF pathway by miR-26a/b overexpression suppressed gastric cancer cell proliferation and migration. Furthermore, miR-26a/b also showed an anti-tumor effect in the xenograft mouse model by suppressing tumor growth and angiogenesis. Conclusions: miR-26a/b could suppress tumor tumorigenesis and angiogenesis by targeting the HGF-VEGF axis and could serve as a potential treatment modality for targeted therapy in the clinical treatment of gastric cancer.


Circulation ◽  
1997 ◽  
Vol 96 (2) ◽  
pp. 636-645 ◽  
Author(s):  
Dorothea I. Axel ◽  
Wolfgang Kunert ◽  
Christoph Göggelmann ◽  
Martin Oberhoff ◽  
Christian Herdeg ◽  
...  

PLoS ONE ◽  
2016 ◽  
Vol 11 (12) ◽  
pp. e0168092 ◽  
Author(s):  
Chin-Chuan Chen ◽  
Chan-Jung Liang ◽  
Yann-Lii Leu ◽  
Yuh-Lien Chen ◽  
Shu-Huei Wang

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