miR-30a-5p suppresses breast tumor growth and metastasis through inhibition of LDHA-mediated Warburg effect

Li, Ling; Liu, Kang; Zhao, Wei; Feng, Yingying; Liu, Wenpeng; Wang, Tao; Mai, Haixing; Huang, Jun; Chen, Siyu; Liang, Yingchun; Han, Juqiang; Xu, Xiaowei; Ye, Qinong

doi:10.1016/j.canlet.2017.04.034

Cited by 166 publications

(109 citation statements)

References 37 publications

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“…[11][12][13] All these findings confirm that LDHA is a promising target for anticancer therapy. 32,33 There are many miRNAs targeting LDHA have been reported, such as miR-30a-5p, 34 In conclusion, findings presented in this study refined our insights into the contributions of LDHA to tumorigenesis, metastasis and progression in GBC. 32,33 There are many miRNAs targeting LDHA have been reported, such as miR-30a-5p, 34 In conclusion, findings presented in this study refined our insights into the contributions of LDHA to tumorigenesis, metastasis and progression in GBC.…”

Section: Discussionsupporting

confidence: 74%

LDHA is a direct target of miR‐30d‐5p and contributes to aggressive progression of gallbladder carcinoma

Chen

et al. 2018

Molecular Carcinogenesis

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Gallbladder cancer (GBC) is the most general biliary tract malignancy, with poor prognosis due to rapid tumor progression and lack of specific symptoms. Lactate dehydrogenase-A (LDHA) can promote Warburg effect to produce lactate and Adenosine Triphosphate (ATP) in aerobic condition, which contributes to oncogenesis metastasis and drug resistance in various cancers. However, the expression and functional role of LDHA in GBC are largely unknown. We determined that LDHA was over-expressed in GBC tumor tissues compared with normal tissues, which was also an independent prognostic factor for the overall survival of GBC patients by tissue microarrays analysis. In addition, RNAi-mediated LDHA silencing could suppress the GBC cell proliferation, invasion, colony formation and glycolysis while promoting cell apoptosis in vitro. Similar results were observed in GBC cells treated with LDHA specific inhibitor FX11. Moreover, we confirmed that knockdown of LDHA could inhibit tumor growth in vivo. Additionally, we found that the 3'-untranslated region (3'-UTR) of LDHA mRNA was the direct target of microRNA-30d-5p (miR-30d-5p), which was low expressed in GBC tissues and associated with poor prognosis of GBC patients. Our findings disclose a novel role for miR-30d-5p/LDHA axis contribute to aggressive progression by reprogramming the metabolic process in GBC cells, and suggest a potential application of miR-30d-5p/LDHA axis in prognosis prediction and GBC treatment.

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Section: Discussionsupporting

confidence: 74%

LDHA is a direct target of miR‐30d‐5p and contributes to aggressive progression of gallbladder carcinoma

Chen

et al. 2018

Molecular Carcinogenesis

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“…Low miR-30a levels were described in aggressive breast cancer cell lines (54), breast cancer patient plasma, and tumor tissue, in association with high stage and decreased RFS and disease-free survival (55,56). The protective effects of miR-30a have been attributed to the downregulation of target genes involved in migration, invasion, apoptosis, and proliferation (57)(58)(59); regulation of epithelial-mesenchymal transition (EMT) by downmodulating vimentin (60); increasing expression of tight-junction proteins claudin 1, 2, and 3 (54); inhibition of cell self-renewal (61); and switching from glycolysis to mitochondrial respiration (62). In agreement with these cell line-based studies, our study is the first to report the association of high miR-30a-3p and -5p levels with improved OS and RFS in TNBC patients.…”

Section: Discussionmentioning

confidence: 99%

Novel prognostic and predictive microRNA targets for triple‐negative breast cancer

et al. 2018

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Triple-negative breast cancers (TNBCs) account for ∼25% of all invasive carcinomas and represent a large subset of aggressive, high-grade tumors. Despite current research focused on understanding the genetic landscape of TNBCs, reliable prognostic and predictive biomarkers remain limited. Although dysregulated microRNAs (miRNAs) have emerged as key players in many cancer types, the role of miRNAs in TNBC disease progression is unclear. We performed miRNA profiling of 51 TNBCs by next-generation sequencing to reveal differentially expressed miRNAs. A total of 228 miRNAs were identified. Three miRNAs (miR-224-5p, miR-375, and miR-205-5p) separated the tumors based on basal status. Six miRNAs (high let-7d-3p, miR-203b-5p, and miR-324-5p; low miR-30a-3p, miR-30a-5p, and miR-199a-5p) were significantly associated with decreased overall survival (OS) and 5 miRNAs (high let-7d-3p; low miR-30a-3p, miR-30a-5p, miR-30c-5p, and miR-128-3p) with decreased relapse-free survival (RFS). On multivariate analysis, high expression of let-7d-3p and low expression of miR-30a were independent predictors of decreased OS and RFS. High expression of miR-95-3p was significantly associated with decreased OS and RFS in patients treated with anthracycline-based chemotherapy. Five miRNAs (let-7d-3p, miR-30a-3p, miR-30c-5p, miR-128-3p, and miR-95-3p) were validated by quantitative RT-PCR. Our findings unveil novel prognostic and predictive miRNA targets for TNBC, including a miRNA signature that predicts patient response to anthracycline-based chemotherapy. This may improve clinical management and/or lead to the development of novel therapies.-Turashvili, G., Lightbody, E. D., Tyryshkin, K., SenGupta, S. K., Elliott, B. E., Madarnas, Y., Ghaffari, A., Day, A., Nicol, C. J. B. Novel prognostic and predictive microRNA targets for triple-negative breast cancer.

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“…miR has emerged as a class of regulatory molecules involving in various biological processes and functional pathways [22]. Its role in the Warburg effect has been gradually revealed [23-25]. We then investigated the involvement of miR in the anti-Warburg effect of 20(S)-Rg3.…”

Section: Discussionmentioning

confidence: 99%

Ginsenoside 20(S)-Rg3 Inhibits the Warburg Effect Via Modulating DNMT3A/ MiR-532-3p/HK2 Pathway in Ovarian Cancer Cells

Zhou

Zheng

et al. 2018

Cell Physiol Biochem

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Background/Aims: The Warburg effect is one of the main energy metabolism features supporting cancer cell growth. 20(S)-Rg3 exerts anti-tumor effect on ovarian cancer partly by inhibiting the Warburg effect. microRNAs are important regulators of the Warburg effect. However, the microRNA regulatory network mediating the anti-Warburg effect of 20(S)-Rg3 was largely unknown. Methods: microRNA deep sequencing was performed to identify the 20(S)-Rg3-influenced microRNAs in SKOV3 ovarian cancer cells. miR-532-3p was overexpressed by mimic532-3p transfection in SKOV3 and A2780 cells or inhibited by inhibitor532-3p transfection in 20(S)-Rg3-treated cells to examine the changes in HK2 and PKM2 expression, glucose consumption, lactate production and cell growth. Dual-luciferase reporter assay was conducted to verify the direct binding of miR-532-3p to HK2. The methylation status in the promoter region of pre-miR-532-3p gene was examined by methylation-specific PCR. Expression changes of key molecules controlling DNA methylation including DNMT1, DNMT3A, DNMT3B, and TET1-3 were examined in 20(S)-Rg3-treated cells. DNMT3A was overexpressed in 20(S)-Rg3-treated cells to examine its influence on miR-532-3p level, HK2 and PKM2 expression, glucose consumption and lactate production. Results: Deep sequencing results showed that 11 microRNAs were increased and 9 microRNAs were decreased by 20(S)-Rg3 in SKOV3 cells, which were verified by qPCR. More than 2-fold increase of miR-532-3p was found in 20(S)-Rg3-treated SKOV3 cells. Forced expression of miR-532-3p reduced HK2 and PKM2 expression, glucose consumption and lactate production in SKOV3 and A2780 ovarian cancer cells. Inhibition of miR-532-3p antagonized the suppressive effect of 20(S)-Rg3 on HK2 and PKM2 expression, glucose consumption and lactate production in ovarian cancer cells. Dual-luciferase reporter assay showed that miR-532-3p directly suppressed HK2 rather than PKM2. miR-532-3p level was controlled by the methylation in the promoter region of its host gene. 20(S)-Rg3 inhibited DNMT3A expression while exerted insignificant effect on DNMT1, DNMT3B and TET1-3. 20(S)-Rg3 reversed DNMT3A-mediated methylation in the promoter of the host gene of miR-532-3p, and thus elevated miR-532-3p level followed by suppression of HK2 and PKM2 expression, glucose consumption and lactate production. Conclusions: 20(S)-Rg3 modulated microRNAs to exert the anti-tumor effect in ovarian cancer. 20(S)-Rg3 lessened the DNMT3A-mediated methylation and promoted the suppression of miR-532-3p on HK2 to antagonize the Warburg effect of ovarian cancer cells.

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miR-30a-5p suppresses breast tumor growth and metastasis through inhibition of LDHA-mediated Warburg effect

Cited by 166 publications

References 37 publications

LDHA is a direct target of miR‐30d‐5p and contributes to aggressive progression of gallbladder carcinoma

LDHA is a direct target of miR‐30d‐5p and contributes to aggressive progression of gallbladder carcinoma

Novel prognostic and predictive microRNA targets for triple‐negative breast cancer

Ginsenoside 20(S)-Rg3 Inhibits the Warburg Effect Via Modulating DNMT3A/ MiR-532-3p/HK2 Pathway in Ovarian Cancer Cells

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