miRNA551b-3p Activates an Oncostatin Signaling Module for the Progression of Triple-Negative Breast Cancer

Parashar, Deepak; Geethadevi, Anjali; Aure, Miriam Ragle; Mishra, Jyotsna; George, Jasmine; Chen, Changliang; Mishra, Manoj K.; Tahiri, Andliena; Zhao, Wei; Nair, Bindu; Lu, Yiling; Mangala, Lingegowda S.; Rodríguez-Aguayo, Cristian; López-Berestein, Gabriel; Camara, Amadou K.S.; Liang, Mingyu; Rader, Janet S.; Ramchandran, Ramani; You, Ming; Sood, Anil K.; Kristensen, Vessela N.; Mills, Gordon B.; Pradeep, Sunila; Chaluvally‐Raghavan, Pradeep

doi:10.1016/j.celrep.2019.11.085

Cited by 67 publications

(63 citation statements)

References 59 publications

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“…These data indicate that the DAT/SLC6A3 is often genetically amplified in many types of cancers and involved in poor prognosis and that it is therefore sensibly targetable by DAT inhibitors such as Benz. It has been shown that STAT3 was able to activate the autocrine feedforward loop by inducing oncostatin M, oncostatin M receptor (OSMR), IL-31, IL-31 receptor, and gp130 [glycoprotein 130, also called IL-6 signal transducer (IL6ST), IL6Rβ, oncostatin M receptor subunit α] [31]. Next, we therefore searched to determine whether the expression of STAT3 and DAT/SLC6A3 were correlated with the expression of other genes related to the STAT and NF-κB signals in colorectal adenocarcinoma patient-derived samples (594 cases).…”

Section: Clinical Significance Of Dat and Statmentioning

confidence: 99%

Antiparkinson Drug Benztropine Suppresses Tumor Growth, Circulating Tumor Cells, and Metastasis by Acting on SLC6A3/DAT and Reducing STAT3

Sogawa

Eguchi

Tran

et al. 2020

Cancers

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Tumor growth, progression, and therapy resistance are crucial factors in the prognosis of cancer. The properties of three-dimensional (3D) tumor-like organoids (tumoroids) more closely resemble in vivo tumors compared to two-dimensionally cultured cells and are therefore effectively used for assays and drug screening. We here established a repurposed drug for novel anticancer research and therapeutics using a 3D tumoroid-based screening system. We screened six pharmacologically active compounds by using an original tumoroid-based multiplex phenotypic screening system with a matrix metalloproteinase 9 (MMP9) promoter-driven fluorescence reporter for the evaluation of both tumoroid formation and progression. The antiparkinson drug benztropine was the most effective compound uncovered by the screen. Benztropine significantly inhibited in vitro tumoroid formation, cancer cell survival, and MMP9 promoter activity. Benztropine also reduced the activity of oncogenic signaling transducers and trans-activators for MMP9, including STAT3, NF-κB, and β-catenin, and the properties of cancer stem cells/cancer-initiating cells. Benztropine and GBR-12935 directly targeted the dopamine transporter DAT/SLC6A3, whose genetic alterations such as amplification were correlated with poor prognosis for cancer patients. Benztropine also inhibited the tumor growth, circulating tumor cell (CTC) number, and rate of metastasis in a tumor allograft model in mice. In conclusion, we propose the repurposing of benztropine for anticancer research and therapeutics that can suppress tumor progression, CTC, and metastasis of aggressive cancers by reducing key pro-tumorigenic factors.

show abstract

Section: Clinical Significance Of Dat and Statmentioning

confidence: 99%

Antiparkinson Drug Benztropine Suppresses Tumor Growth, Circulating Tumor Cells, and Metastasis by Acting on SLC6A3/DAT and Reducing STAT3

Sogawa

Eguchi

Tran

et al. 2020

Cancers

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show abstract

“…MicroRNA plays a broad range of oncogenic functions in TNBC including cell proliferation, apoptosis, migration, metastasis, epithelial mesenchymal transition (EMT) process, and angiogenesis 14 . For example, miR551b-3p is aberrantly expressed in TNBC and targeting miR-551b with anti-miR551b-3p reduces tumor growth and metastasis 15 . Additionally, miR-221 transfer from TNBC cells via microvesicles induces EMT and promotes the malignant potential of recipient cells 16 .…”

Section: Introductionmentioning

confidence: 99%

A miR-210-3p regulon that controls the Warburg effect by modulating HIF-1α and p53 activity in triple-negative breast cancer

Wei

et al. 2020

Cell Death Dis

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Reprogrammed energy metabolism, especially the Warburg effect (aerobic glycolysis), is an emerging hallmark of cancer. Different from other breast cancer subtypes, triple-negative breast cancer (TNBC) exhibits high metabolic remodeling, increased aggressiveness and lack of targeted therapies. MicroRNAs (miRNA) are essential to TNBC malignant phenotypes. However, little is known about the contribution of miRNA to aerobic glycolysis in TNBC. Through an integrated analysis and functional verification, we reported that several miRNAs significantly correlates to the Warburg effect in TNBC, including miR-210-3p, miR-105-5p, and miR-767-5p. Ectopic expression of miR-210-3p enhanced glucose uptake, lactate production, extracellular acidification rate, colony formation ability, and reduced serum starvation-induced cell apoptosis. Moreover, GPD1L and CYGB were identified as two functional mediators of miR-210-3p in TNBC. Mechanistically, miR-210-3p targeted GPD1L to maintain HIF-1α stabilization and suppressed p53 activity via CYGB. Ultimately, miR-210-3p facilitated aerobic glycolysis through modulating the downstream glycolytic genes of HIF-1α and p53. Taken together, our results decipher miRNAs that regulate aerobic glycolysis and uncover that miR-210-3p specifically contributes to the Warburg effect in TNBC.

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“…is often genetically amplified in many types of cancers and involved in poor prognosis and therefore sensibly targetable by DAT inhibitors such as Benz. It has been shown that STAT3 was able to activate the autocrine feedforward loop by inducing oncostatin M, oncostatin M receptor (OSMR), IL-31, IL-31 receptor, and gp130 [glycoprotein 130, also called IL-6 signal transducer (IL6ST), IL6Rβ, oncostatin M receptor subunit α] [26]. We therefore next searched to determine whether the expression of STAT3 and DAT/SLC6A3 were correlated with the expression of other genes related to the STAT and NF-κB signals in colorectal adenocarcinoma patient-derived samples (594 cases).…”

Section: Clinical Significance Of Dat and Statmentioning

confidence: 99%

Antiparkinson Drug Benztropine Suppresses Tumor Growth, Circulating Tumor Cells, and Metastasis by Acting on SLC6A3 and Reducing STAT3

Sogawa¹,

Tran²,

Imamura³

et al. 2020

Preprint

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Tumor growth, progression, and therapy resistance are crucial factors in the prognosis of cancer. Properties of three-dimensional tumor-like organoids (tumoroids) more closely resemble in vivo tumors compared to two-dimensionally cultured cells and are therefore effectively used for assays and drug screening. We here established a repurposed drug for novel anticancer research and therapeutics using a tumoroid-based screening system. We screened 6 pharmacologically active compounds by using an original tumoroid-based multiplex phenotypic screening system with matrix metalloproteinase 9 (MMP9) promoter-driven fluorescence reporter for the evaluation of both tumoroid formation and progression. The effects of one of the hit compounds were examined on tumor formation and progression in vitro and in vivo. Antiparkinson drug benztropine was the most effective compound uncovered by the screen. Benztropine significantly inhibited in vitro tumoroid formation, cancer cell survival, and MMP9 promoter activity. Benztropine also reduced the activity of oncogenic signaling transducers and trans-activators for MMP9, including STAT3, NF-κB, and β-catenin, and properties of cancer stem cells / cancer-initiating cells. Benztropine and GBR-12935 directly targeted the dopamine transporter DAT/SLC6A3, whose genetic alterations such as amplification were correlated with poor prognosis for cancer patients. Benztropine also inhibited tumor growth, circulating tumor cell (CTC) number, and rate of metastasis in a tumor allograft model in mice. In conclusion, we propose the repurposing of benztropine for anticancer research and therapeutics that can suppress tumor progression, CTC, and metastasis of aggressive cancers by reducing key pro-tumorigenic factors.

show abstract

miRNA551b-3p Activates an Oncostatin Signaling Module for the Progression of Triple-Negative Breast Cancer

Cited by 67 publications

References 59 publications

Antiparkinson Drug Benztropine Suppresses Tumor Growth, Circulating Tumor Cells, and Metastasis by Acting on SLC6A3/DAT and Reducing STAT3

Antiparkinson Drug Benztropine Suppresses Tumor Growth, Circulating Tumor Cells, and Metastasis by Acting on SLC6A3/DAT and Reducing STAT3

A miR-210-3p regulon that controls the Warburg effect by modulating HIF-1α and p53 activity in triple-negative breast cancer

Antiparkinson Drug Benztropine Suppresses Tumor Growth, Circulating Tumor Cells, and Metastasis by Acting on SLC6A3 and Reducing STAT3

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