The long noncoding RNA KCNQ1DN suppresses the survival of renal cell carcinoma cells through downregulating c-Myc

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Abstract

Background: Long noncoding RNAs (lncRNAs) have been demonstrated to play essential roles in renal cell carcinoma (RCC). However, the role of lncRNA KCNQ1DN in RCC remains unclear.

Methods: The expression of KCNQ1DN in RCC and the corresponding adjacent tissues was measured by qPCR. RNA fluorescence in situ hybridization (FISH) assay, methylation analysis, reporter gene assays and functional tests were performed to reveal the effects of KCNQ1DN on RCC.

Results: In the present study, we found that lncRNA KCNQ1DN was notably decreased in RCC tissues and cell lines. RNA FISH assay showed that KCNQ1DN mainly localized to the cytoplasm. Methylation analysis revealed that the proximal region of KCNQ1DN promoter was hypermethylated in RCC tissues relative to the adjacent normal ones. Functional studies clarified that KCNQ1DN repressed the RCC cell growth and cell cycle progression. Mechanistically, KCNQ1DN inhibited the expression of c-Myc, which might further upregulate cyclin D1 and suppress p27 at mRNA and protein levels in RCC cells. Reporter gene assays revealed that the transcriptional activity of c-Myc promoter was inhibited by KCNQ1DN. The in vivo experiments in nude mice showed that KCNQ1DN overexpression dramatically repressed the growth of xenograft tumors and the expression of corresponding c-Myc.

Conclusion: These results indicated that KCNQ1DN inhibit the growth of RCC cells in vitro and in vivo through repressing the oncogene c-myc, suggesting that KCNQ1DN may serve as a novel target for the treatment of RCC.

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Most cited references 14

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MYC and metabolism on the path to cancer.

Annie Hsieh, Zandra E Walton, Brian J. Altman … (2015)

The MYC proto-oncogene is frequently deregulated in human cancers, activating genetic programs that orchestrate biological processes to promote growth and proliferation. Altered metabolism characterized by heightened nutrients uptake, enhanced glycolysis and glutaminolysis and elevated fatty acid and nucleotide synthesis is the hallmark of MYC-driven cancer. Recent evidence strongly suggests that Myc-dependent metabolic reprogramming is critical for tumorigenesis, which could be attenuated by targeting specific metabolic pathways using small drug-like molecules. Understanding the complexity of MYC-mediated metabolic re-wiring in cancers as well as how MYC cooperates with other metabolic drivers such as mammalian target of rapamycin (mTOR) will provide translational opportunities for cancer therapy.

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Pancreatic cancer risk variant in LINC00673 creates a miR-1231 binding site and interferes with PTPN11 degradation.

Jian Zheng, Xudong Huang, Wen-wen Tan … (2016)

Genome-wide association studies have identified several loci associated with pancreatic cancer risk; however, the mechanisms by which genetic factors influence the development of sporadic pancreatic cancer remain largely unknown. Here, by using genome-wide association analysis and functional characterization, we identify a long intergenic noncoding RNA (lincRNA), LINC00673, as a potential tumor suppressor whose germline variation is associated with pancreatic cancer risk. LINC00673 is able to reinforce the interaction of PTPN11 with PRPF19, an E3 ubiquitin ligase, and promote PTPN11 degradation through ubiquitination, which causes diminished SRC-ERK oncogenic signaling and enhanced activation of the STAT1-dependent antitumor response. A G>A change at rs11655237 in exon 4 of LINC00673 creates a target site for miR-1231 binding, which diminishes the effect of LINC00673 in an allele-specific manner and thus confers susceptibility to tumorigenesis. These findings shed new light on the important role of LINC00673 in maintaining cell homeostasis and how its germline variation might confer susceptibility to pancreatic cancer.

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Landmarks in the diagnosis and treatment of renal cell carcinoma.

Antonio Finelli, J. Bhatt (2014)

The most common renal cancer is renal cell carcinoma (RCC), which arises from the renal parenchyma. The global incidence of RCC has increased over the past two decades by 2% per year. RCC is the most lethal of the common urological cancers: despite diagnostic advances, 20-30% of patients present with metastatic disease. A clearer understanding of the genetic basis of RCC has led to immune-based and targeted treatments for this chemoresistant cancer. Despite promising results in advanced disease, overall response rates and durable complete responses are rare. Surgery remains the main treatment modality, especially for organ-confined disease, with a selective role in advanced and metastatic disease. Smaller tumours are increasingly managed with biopsy, minimally invasive interventions and surveillance. The future promises multimodal, integrated and personalized care, with further understanding of the disease leading to new treatment options.

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Author and article information

Journal

Journal ID (nlm-ta): J Cancer

Journal ID (iso-abbrev): J Cancer

Journal ID (publisher-id): jca

Title: Journal of Cancer

Publisher: Ivyspring International Publisher (Sydney )

ISSN (Electronic): 1837-9664

Publication date Collection: 2019

Publication date (Electronic): 19 August 2019

Volume: 10

Issue: 19

Pages: 4662-4670

Affiliations

[1 ]Central Laboratory, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing 400037, China;

[2 ]Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Army Medical University (Third Military Medical University), Chongqing 400038, China;

[3 ]Department of Urology, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing 400037, China.

[4 ]Nursing division, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing 400037, China.

Author notes

✉ Corresponding authors: Pro. Kebin Zhang, Central Laboratory, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing 400037, China. Tel.&Fax: 86-23-68755381, E-mail: zhangkebin12@ 123456163.com ; Pro. Fengtian He, Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Army Medical University (Third Military Medical University), 30 Gaotanyan, Shapingba, Chongqing 400038, China. Tel.&Fax: 86-23-68771340, E-mail: hefengtian66@ 123456163.com ; Pro. Hongming Miao, Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Army Medical University (Third Military Medical University), 30 Gaotanyan, Shapingba, Chongqing 400038, China. Tel.: 86-13678484686, E-mail: hongmingmiao@ 123456sina.com .

^*These authors contributed equally to this work.

Competing Interests: The authors have declared that no competing interest exists.

Article

Publisher ID: jcav10p4662

DOI: 10.7150/jca.29280

PMC ID: 6746116

PubMed ID: 31528231

SO-VID: 3083565a-9eff-425f-965a-4312da40482a

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This is an open access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

The long noncoding RNA KCNQ1DN suppresses the survival of renal cell carcinoma cells through downregulating c-Myc

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Karger: Oncology

Most cited references 14

MYC and metabolism on the path to cancer.

Pancreatic cancer risk variant in LINC00673 creates a miR-1231 binding site and interferes with PTPN11 degradation.

Landmarks in the diagnosis and treatment of renal cell carcinoma.

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