Long noncoding RNA DANCR, working as a competitive endogenous RNA, promotes ROCK1-mediated proliferation and metastasis via decoying of miR-335-5p and miR-1972 in osteosarcoma

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Abstract

Background

Accumulating evidences indicate that non-coding RNAs (ncRNAs) including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) acting as crucial regulators in osteosarcoma (OS). Previously, we reported that Rho associated coiled-coil containing protein kinase 1 (ROCK1), a metastatic-related gene was negatively regulated by microRNA-335-5p (miR-335-5p) and work as an oncogene in osteosarcoma. Whether any long non-coding RNAs participate in the upstream of miR-335-5p/ROCK1 axial remains unclear.

Methods

Expression of differentiation antagonizing non-protein coding RNA (DANCR) and miR-335-5p/miR-1972 in osteosarcoma tissues were determined by a qRT-PCR assay and an ISH assay. Osteosarcoma cells’ proliferation and migration/invasion ability changes were measured by a CCK-8/EDU assay and a transwell assay respectively. ROCK1 expression changes were checked by a qRT-PCR assay and a western blot assay. Targeted binding effects between miR-335-5p/miR-1972 and ROCK1 or DANCR were verified by a dual luciferase reporter assay and a RIP assay. In vivo experiments including a nude formation assay as well as a CT scan were applied to detect tumor growth and metastasis changes in animal level.

Results

In the present study, an elevated DNACR was found in osteosarcoma tissue specimens and in osteosarcoma cell lines, and the elevated DNACR was closely correlated with poor prognosis in clinical patients. Functional experiments illustrated that a depression of DANCR suppressed ROCK1-mediated proliferation and metastasis in osteosarcoma cells. The results of western blot assays and qRT-PCR assays revealed that DANCR regulated ROCK1 via crosstalk with miR-335-5p and miR-1972. Further cellular behavioral experiments demonstrated that DNACR promoted ROCK1-meidated proliferation and metastasis through decoying both miR-335-5p and miR-1972. Finally, the outcomes of in vivo animal models showed that DANCR promoted tumor growth and lung metastasis of osteosarcoma.

Conclusions

LncRNA DANCR work as an oncogene and promoted ROCK1-mediated proliferation and metastasis through acting as a competing endogenous RNA (ceRNA) in osteosarcoma.

Electronic supplementary material

The online version of this article (10.1186/s12943-018-0837-6) contains supplementary material, which is available to authorized users.

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Most cited references 25

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Long non‐coding RNA TUG1 promotes migration and invasion by acting as a ceRNA of miR‐335‐5p in osteosarcoma cells

Yong Wang, Tao Yang, Zhen Zhang … (2017)

Long non‐coding RNA (lncRNA) have been the focus of increasing attention due to the role they play in many diseases, including osteosarcoma. The function of taurine upregulated gene 1 (TUG1) and its mechanism in osteosarcoma remain unclear. In our research, we found that TUG1 was elevated and correlated with a poor prognosis in osteosarcoma patients. In addition, the following functional experiment showed that decreased TUG1 could remarkably inhibit osteosarcoma cell migration and invasion, indicating that TUG1 functioned as an oncogene in osteosarcoma. Moreover, we revealed that TUG1 and Rho‐associated coiled‐coil‐containing protein kinase 1 (ROCK1), a metastasis‐related gene targeted by microRNA‐335‐5p (miR‐335‐5p), had the same miR‐335‐5p combining site. The subsequent luciferase assay verified TUG1 was a target of miR‐335‐5p. Furthermore, the results of a real‐time quantitative PCR showed that TUG1 and miR‐335‐5p could affect each other's expression. respectively. Finally, we affirmed that TUG1 affected ROCK1 expression and ROCK1‐mediated migration/invasion by working as a competitive endogenous RNA (ceRNA) via miR‐335‐5p. In summary, the findings of this study, based on ceRNA theory, combining the research foundation of miR‐335‐5p and ROCK1, and taking TUG1 as a new study point, provide new insight into molecular‐level reversing migration and invasion of osteosarcoma.

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MicroRNAs and Potential Targets in Osteosarcoma: Review

Valerie B. Sampson, Soonmoon Yoo, Asmita Kumar … (2015)

Osteosarcoma is the most common bone cancer in children and young adults. Surgery and multi-agent chemotherapy are the standard treatment regimens for this disease. New therapies are being investigated to improve overall survival in patients. Molecular targets that actively modulate cell processes, such as cell-cycle control, cell proliferation, metabolism, and apoptosis, have been studied, but it remains a challenge to develop novel, effective-targeted therapies to treat this heterogeneous and complex disease. MicroRNAs (miRNAs) are small non-coding RNAs that play critical roles in regulating cell processes including growth, development, and disease. miRNAs function as oncogenes or tumor suppressors to regulate gene and protein expression. Several studies have demonstrated the involvement of miRNAs in the pathogenesis of osteosarcoma with the potential for development in disease diagnostics and therapeutics. In this review, we discuss the current knowledge on the role of miRNAs and their target genes and evaluate their potential use as therapeutic agents in osteosarcoma. We also summarize the efficacy of inhibition of oncogenic miRNAs or expression of tumor suppressor miRNAs in preclinical models of osteosarcoma. Recent progress on systemic delivery as well as current applications for miRNAs as therapeutic agents has seen the advancement of miR-34a in clinical trials for adult patients with non-resectable primary liver cancer or metastatic cancer with liver involvement. We suggest a global approach to the understanding of the pathogenesis of osteosarcoma may identify candidate miRNAs as promising biomarkers for this rare disease.

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Time-trends on incidence and survival in a nationwide and unselected cohort of patients with skeletal osteosarcoma

Kjetil Berner, Tom B⊘rge Johannesen, Aasmund Berner … (2014)

Abstract Background This study describes time-trends on epidemiology, subtypes and histopathological entities of osteosarcoma (OS) in a nationwide and unselected cohort of OS patients in Norway between 1975 and 2009. Few nationwide studies are published, and we still have particularly limited knowledge regarding patients not included in clinical trials comprising about half of the OS population. Method Histologically verified skeletal OS for all subgroups were included, resulting in 473 eligible cases from a total of 702 evaluated patients. To ensure completeness, the present cohort was based on all cases reported to the Norwegian Cancer Registry, complemented with data from all Norwegian hospitals involved in sarcoma management. Survival analyses were performed with overall and sarcoma-specific survival as endpoints. Results Mean annual age-standard incidence amounted to about 3.8 per million in male and 2.8 per million in female with no clear time-trends. The male to female ratio was 1.4. Peak incidence was observed in the second decade for both genders. Conventional OS comprised 71.2% of all cases, while low grade OS represented 10.4% and telangiectatic OS only 1.3%. The most common primary site of OS was femur and tibia, respectively. The axial to appendicular ratio increased with the age. The overall 10-year survival did increase from about 30% during the late 1970s to around 50% 20 years later, with no subsequent improvement during the last two decades. Axial tumours, age above 40 years and overt metastatic disease at time of diagnosis were all negative prognostic factors. Conclusion No improvement in the overall survival for OS since the 1990s was documented. The survival rates are still poor for elderly people, patients with axial disease and in the primary metastatic setting. The average incidence rate of skeletal OS in Norway was in line with international figures.

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Author and article information

Contributors

Yong Wang:

ORCID: http://orcid.org/0000-0003-3674-9403

+86-24-85715382 , wy_landy1116@163.com

Journal

Journal ID (nlm-ta): Mol Cancer

Journal ID (iso-abbrev): Mol. Cancer

Title: Molecular Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1476-4598

Publication date (Electronic): 12 May 2018

Publication date PMC-release: 12 May 2018

Publication date Collection: 2018

Volume: 17

Electronic Location Identifier: 89

Affiliations

[1 ]GRID grid.459424.a, 4th Department of Orthopedic Surgery, , Central Hospital affiliated to Shenyang Medical College, ; No.5, South Seven West Road, Tiexi District, Shenyang, Liaoning 110024 People’s Republic of China

[2 ]GRID grid.459424.a, Department of Surgical Oncology, , Central Hospital affiliated to Shenyang Medical College, ; Shenyang, People’s Republic of China

[3 ]GRID grid.459424.a, 2nd Department of Cardiology, , Central Hospital affiliated to Shenyang Medical College, ; Shenyang, People’s Republic of China

[4 ]ISNI 0000 0004 1936 973X, GRID grid.5252.0, Institute for Cardiovascular Prevention, , Ludwig-Maximilians-University, ; Munich, Germany

[5 ]GRID grid.459424.a, 1st Department of Hand Surgery, , Central Hospital affiliated to Shenyang Medical College, ; Shenyang, People’s Republic of China

[6 ]ISNI 0000 0004 1798 5889, GRID grid.459742.9, Department of Pathology, , Liaoning Cancer Hospital & Institute, ; Shenyang, People’s Republic of China

[7 ]GRID grid.452435.1, Department of Nuclear Medicine, , The First Affiliated Hospital of Dalian Medical University, ; Dalian, 116011 People’s Republic of China

Author information

Yong Wang http://orcid.org/0000-0003-3674-9403

Article

Publisher ID: 837

DOI: 10.1186/s12943-018-0837-6

PMC ID: 5948795

PubMed ID: 29753317

SO-VID: 7652cb22-3b30-45a9-803a-a4f82ac1acc5

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 17 February 2018

Date accepted : 25 April 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81502333

Award Recipient : Yong Wang

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: lncrna dancr,mir-335-5p/mir-1972,osteosarcoma,proliferation/metastasis,cerna

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: lncrna dancr, mir-335-5p/mir-1972, osteosarcoma, proliferation/metastasis, cerna

Long noncoding RNA DANCR, working as a competitive endogenous RNA, promotes ROCK1-mediated proliferation and metastasis via decoying of miR-335-5p and miR-1972 in osteosarcoma

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Most cited references 25

Long non‐coding RNA TUG1 promotes migration and invasion by acting as a ceRNA of miR‐335‐5p in osteosarcoma cells

MicroRNAs and Potential Targets in Osteosarcoma: Review

Time-trends on incidence and survival in a nationwide and unselected cohort of patients with skeletal osteosarcoma

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