Linc-RoR promotes MAPK/ERK signaling and confers estrogen-independent growth of breast cancer

Autor: Wanxin Peng, Yin-Yuan Mo, Aihua Gong, Jianguo Huang, Liu Yang
Rok vydání: 2017
Předmět:
0301 basic medicine
MAPK/ERK pathway
Cancer Research
medicine.medical_specialty
Estrogen-independent growth
Antineoplastic Agents
Hormonal
Blotting
Western
Breast Neoplasms
Biology
DUSP7
lcsh:RC254-282
03 medical and health sciences
0302 clinical medicine
Breast cancer
Downregulation and upregulation
Internal medicine
Linc-RoR
Dual-specificity phosphatase
medicine
Humans
Cell Proliferation
Reverse Transcriptase Polymerase Chain Reaction
Research
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
medicine.disease
3. Good health
Tamoxifen
ERK
030104 developmental biology
Endocrinology
Oncology
Drug Resistance
Neoplasm
030220 oncology & carcinogenesis
biology.protein
Cancer research
MCF-7 Cells
Molecular Medicine
Phosphorylation
Dual-Specificity Phosphatases
RNA
Long Noncoding
Signal transduction
CRISPR-Cas Systems
medicine.drug
Signal Transduction
Zdroj: Molecular Cancer
Molecular Cancer, Vol 16, Iss 1, Pp 1-11 (2017)
ISSN: 1476-4598
Popis: Background The conversion from estrogen-dependent to estrogen-independent state of ER+ breast cancer cells is the key step to promote resistance to endocrine therapies. Although the crucial role of MAPK/ERK signaling pathway in estrogen-independent breast cancer cell growth is well established, the underlying mechanism is not fully understood. Methods In this study, we profiled lncRNA expression against a focused group of lncRNAs selected from lncRNA database. CRISPR/Cas9 was employed to knockout (KO) linc-RoR in MCF-7 cells, while rescue experiments were carried out to re-express linc-RoR in KO cells. Colony formation and MTT assays were used to examine the role of linc-RoR in estrogen-independent growth and tamoxifen resistance. Western blot and qRT-PCR were used to determine the change of protein and lncRNA levels, respectively. The expression of DUSP7 in clinical specimens was downloaded from Oncomine (www.oncomine.org) and the dataset from Kaplan-Meier Plotter (http://kmplot.com) was used to analyze the clinical outcomes in relation to DUSP7. Results We identified that linc-RoR functions as an onco-lncRNA to promote estrogen-independent growth of ER+ breast cancer. Under estrogen deprivation, linc-RoR causes the upregulation of phosphorylated MAPK/ERK pathway which in turn activates ER signaling. Knockout of linc-RoR abrogates estrogen deprivation-induced ERK activation as well as ER phosphorylation, whereas re-expression of linc-RoR restores all above phenotypes. Moreover, we show that the ERK-specific phosphatase Dual Specificity Phosphatase 7 (DUSP7), also known as MKP-X, is involved in linc-RoR KO-induced repression of MAPK/ERK signaling. Interestingly, linc-RoR KO increases the protein stability of DUSP7, resulting in repression of ERK phosphorylation. Clinical data analysis reveal that DUSP7 expression is lower in ER+ breast cancer samples than that in ER- breast cancer. Moreover, downregulation of DUSP7 expression is associated with poor patient survival. Conclusion Taken together, these results suggest that linc-RoR promotes estrogen-independent growth and activation of MAPK/ERK pathway of breast cancer cells by regulating the ERK-specific phosphatase DUSP7. Thus, this study might help not only in establishing a role for linc-RoR in estrogen-independent and tamoxifen resistance of ER+ breast cancer, but also suggesting a link between linc-RoR and MAPK/ERK pathway. Electronic supplementary material The online version of this article (10.1186/s12943-017-0727-3) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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