A p53/miR-30a/ZEB2 axis controls triple negative breast cancer aggressiveness

Gennaro, Alessandra di; Damiano, Valentina; Brisotto, Giulia; Armellin, Michela; Perin, Tiziana; Zucchetto, Antonella; Guardascione, Michela; Spaink, Herman P.; Doglioni, Claudio; Snaar-Jagalska, B. Ewa; Santarosa, Manuela; Maestro, Roberta

doi:10.1038/s41418-018-0103-x

Cited by 80 publications

(75 citation statements)

References 60 publications

(84 reference statements)

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“…miR‐30a has been shown to play an inhibitory role in many cancers, such as cancers of the colon, breast, and lung 38‐40 . miR‐30a has also been previously reported to function as a tumor suppressor in PCa 12,13,15,16,41 .…”

Section: Discussionmentioning

confidence: 98%

miR‐30a inhibits androgen‐independent growth of prostate cancer via targeting MYBL2, FOXD1, and SOX4

et al. 2020

The Prostate

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Background: Castrate-resistant prostate cancer (CRPC) is an aggressive and lethal disease. The pathogenesis of CRPC is not fully understood and novel therapeutic targets need to be identified to improve the patients' prognosis. has been demonstrated to be a tumor suppressor in many types of solid malignancies. However, its role in androgen-independent (AI) growth of prostate cancer (PCa) received limited attention as yet. Methods:The clinical association of miR-30a and its potential targets with AI growth was characterized by bioinformatics analyses. Regulation of cell proliferation and colony formation rates by miR-30a were tested using PCa cell models. Xenograft models were used to measure the regulation of prostate tumor growth by miR-30a.The real-time quantitative polymerase chain reaction was used to validate whether miR-30a and its targets regulate cell cycle control genes and androgen receptor (AR)-dependent transcription. Bioinformatics tools, Western blot, and luciferase reporter assays were utilized to identify miR-30a targets. Results: Bioinformatic analysis showed that low expression of miR-30a is associated with castration resistance of PCa patients and poor outcomes. Transfection of miR-30a mimics inhibited the AI growth of PCa cells in vitro and in vivo. Upregulation of miR-30a in 22RV1 cells altered the expression of cell cycle control genes and AR-mediated transcription, while downregulation of miR-30a in LNCaP cells had the opposite effects to AR-mediated transcription. MYBL2, FOXD1, and SOX4 were identified as miR-30a targets. Downregulation of MYBL2, FOXD1, and SOX4 affected the expression of cell cycle control genes and AR-mediated transcription and suppressed the AI growth of 22RV1 cells. Conclusions: Our results suggest that miR-30a inhibits AI growth of PCa by targeting MYBL2, FOXD1, and SOX4. They provide novel insights into developing new treatment strategies for CRPC. K E Y W O R D S castration-resistant prostate cancer, FOXD1, miR-30a, MYBL2, SOX4

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Section: Discussionmentioning

confidence: 98%

miR‐30a inhibits androgen‐independent growth of prostate cancer via targeting MYBL2, FOXD1, and SOX4

et al. 2020

The Prostate

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“…Expression of miR-30a has been shown to be markedly reduced in patients suffering from triple-negative breast cancer with mutations in the TP53 gene, and this expression was negatively correlated with patient survival. Inactivation of p53 in these patients was associated with reduced miR-30a expression and an associated decrease in miR-30a-mediated suppression of ZEB2 expression, thereby leading to enhanced breast cancer cell plasticity, migration, and metastasis [6]. Other targets of miR-30a in breast cancer have also been identified as potential links between this miRNA and the regulation of metastatic progression, including vimentin, MTDH, and Eya2 [11,23,28].…”

Section: Biomed Research Internationalmentioning

confidence: 93%

“…Recently, accumulating evidence indicates that miRNAs may act as either tumor suppressors or oncogenes in the genesis of diverse cancer types [3,4]. The dysregulated expression of certain miRNAs, including miR-30 family members, has been closely linked to the onset and progression of breast cancer [5][6][7]. The miR-30 family includes 6 mature miRNAs (miR-30a, miR-30b, miR-30c-1, miR-30c-2, miR-30d, and miR-30e) that are separately encoded on chromosomes 1, 6, and 8.…”

Section: Introductionmentioning

confidence: 99%

“…Among the miR-30 members, miR-30a had drawn much attention due to its functions in inhibiting primary tumor growth or metastasis formation in several cancer types, especially in breast cancer [8][9][10][11][12]. When miR-30a expression was decreased in breast tumors, this was linked with higher rates of lymph node metastasis, p53 inactivation, and poorer patient prognosis [6]. In other studies, miR-30b was shown to suppress CCNE2 expression in HER2-positive breast cancer cells, thereby suppressing their growth and inducing G1 phase cell cycle arrest [13].…”

Section: Introductionmentioning

confidence: 99%

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Genetic Variations in miR-30 Family Member Regulatory Regions Are Associated with Breast Cancer Risk in a Chinese Population

Zhou

Wang

Liu

et al. 2020

BioMed Research International

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MicroRNAs (miRNAs) of the miR-30 family are closely linked with tumor metastasis and play key roles in the complex malignant phenotypes of cancers by targeting many tumor-related genes. Deregulated expression of miR-30 family members has been commonly observed in breast cancer. However, associations between the genetic variants in the regulatory region of miR-30 family and the risk of breast cancer are still limited, especially in the Chinese Han population. In the present study, we conducted a case-control analysis wherein 1064 breast cancer patients and 1073 healthy controls underwent genotyping of 10 SNPs in the regulatory region of miR-30 family members. Multivariate logistic regression analyses illustrated that the rs763354 variant in the miR-30a regulatory region was linked with a significant decrease in breast cancer risk in an additive model (adjusted OR = 0:86, 95% CI: 0.75-0.98, P = 0:022). Further, eQTL analyses also indicated that this SNP was associated with miR-30a expression levels in breast cancer samples compiled in the TCGA database (P = 0:020). The Kaplan-Meier plotter showed that breast cancer patients with higher miR-30a expression have significantly better outcomes than do patients expressing low levels of this miRNA (HR = 0:75, 95% CI: 0.61-0.91, P = 0:0041). Together, these findings suggest that the miR-30a rs763354 SNP is an important regulator of breast cancer risk, thus making it a potentially viable prognostic biomarker and one that can be used to guide therapeutic treatment in affected patients.

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“…In our previous study, we identified ZEB2 as a pivotal biomarker in glioma that promotes proliferation, migration, and invasion by inducing the epithelialmesenchymal transition (EMT) process and cell cycle progression (19). A recent study showed that ZEB2 was inhibited by several miRNAs, such as miR-153 (20), miR-155 (21), and miR-30a (22), and these interactions significantly suppressed the EMT process. On the other hand, ZEB2 was also found to regulate miRNA expression as a repressive transcription factor.…”

Section: Introductionmentioning

confidence: 99%

Oncogenic ZEB2/miR-637/HMGA1 signaling axis targeting vimentin promotes the malignant phenotype of glioma

Zeng

Que

Lin

et al. 2020

Preprint

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Background Glioma is the most common primary tumor of the central nervous system. We previously confirmed that zinc finger E-box binding homeobox (ZEB) 2 promotes the malignant progression of glioma, while microRNA-637 (miR-637) is associated with favorable prognosis in glioma. This study investigated the potential interaction between ZEB2 and miR-637 and its downstream signaling pathway in glioma. Methods Chromatin immunoprecipitation, luciferase reporter, and electrophoretic mobility shift assays were used to confirm ZEB2 binding to miR-637. Microarray and bioinformatic analyses were used to investigate targets of miR-637. MTT and EdU assays, transwell assays, and Boyden assays were utilized to assess cell viability, migration, and invasion, respectively. A subcutaneous xenograft model was utilized for analyzing the role of miR-637/high mobility group A1 (HMGA1) interaction in vivo. Immunohistochemistry staining of clinical samples and bioinformatic analysis of the Chinese Glioma Genome Atlas and The Cancer Genome Atlas databases were performed to further confirm the ZEB2/miR-637/HMGA1/vimentin axis. Results ZEB2 was bound directly bind to the E-box elements in the miR-637 promoter and promoted cell proliferation, migration, and invasion via miR-637 downregulation. Subsequent screening confirmed that HMGA1 was a direct target of miR-637, while miR-637 could propagate the malignant phenotype of glioma by suppressing HMGA1 both in vitro and in vivo. Furthermore, the interaction between cytoplasmic HMGA1 and vimentin was observed, and vimentin inhibition could abolish increased migration and invasion induced by HMGA1 overexpression. Notably, the ZEB2/miR-637/HMGA1/vimentin axis was also evident in glioma tissue samples and public glioma datasets, while both HMGA1 and vimentin were associated with an unfavorable prognosis in glioma. Additionally, upregulated HMGA1 and vimentin were found in isocitrate dehydrogenase (IDH) wild-type and 1p/19q non-codeletion diffusely infiltrating glioma. Conclusions We identified an oncogenic ZEB2/miR-637/HMGA1 signaling axis targeting vimentin that promotes both migration and invasion in glioma. This not only extends the current understanding of miR-637 regulation in glioma, but also unravels a novel signaling pathway that integrates a transcriptional factor, microRNA, and a chromatin remodeling factor to modulate the malignant phenotype of glioma.

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A p53/miR-30a/ZEB2 axis controls triple negative breast cancer aggressiveness

Cited by 80 publications

References 60 publications

miR‐30a inhibits androgen‐independent growth of prostate cancer via targeting MYBL2, FOXD1, and SOX4

miR‐30a inhibits androgen‐independent growth of prostate cancer via targeting MYBL2, FOXD1, and SOX4

Genetic Variations in miR-30 Family Member Regulatory Regions Are Associated with Breast Cancer Risk in a Chinese Population

Oncogenic ZEB2/miR-637/HMGA1 signaling axis targeting vimentin promotes the malignant phenotype of glioma

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