The Epithelial–Mesenchymal Transcription Factor SNAI1 Represses Transcription of the Tumor Suppressor miRNA let-7 in Cancer

Wang, Hanmin; Chirshev, Evgeny; Hojo, Nozomi; Suzuki, Tise; Bertucci, Antonella; Pierce, Michael; Perry, Christopher; Wang, Ruining; Zink, Jeffrey I.; Glackin, Carlotta A.; Ioffe, Yevgeniya; Unternaehrer, Juli

doi:10.3390/cancers13061469

Cited by 19 publications

(18 citation statements)

References 69 publications

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“…The EMT transcription factor SNAI1 represses transcription of the TS miRNA Let-7 in cancer. SNAI1 bind let-7 family promoters to inhibit miRNA transcription (27).…”

Section: Ts Mirna Promote Apoptosis In Cancermentioning

confidence: 99%

Tumor Suppressor miRNA in Cancer Cells and the Tumor Microenvironment: Mechanism of Deregulation and Clinical Implications

Otmani

Lewalle

2021

Front. Oncol.

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MicroRNAs (miRNAs) are noncoding RNAs that have been identified as important posttranscriptional regulators of gene expression. miRNAs production is controlled at multiple levels, including transcriptional and posttranscriptional regulation. Extensive profiling studies have shown that the regulation of mature miRNAs expression plays a causal role in cancer development and progression. miRNAs have been identified to act as tumor suppressors (TS) or as oncogenes based on their modulating effect on the expression of their target genes. Upregulation of oncogenic miRNAs blocks TS genes and leads to tumor formation. In contrast, downregulation of miRNAs with TS function increases the translation of oncogenes. Several miRNAs exhibiting TS properties have been studied. In this review we focus on recent studies on the role of TS miRNAs in cancer cells and the tumor microenvironment (TME). Furthermore, we discuss how TS miRNA impacts the aggressiveness of cancer cells, with focus of the mechanism that regulate its expression. The study of the mechanisms of miRNA regulation in cancer cells and the TME may paved the way to understand its critical role in the development and progression of cancer and is likely to have important clinical implications in a near future. Finally, the potential roles of miRNAs as specific biomarkers for the diagnosis and the prognosis of cancer and the replacement of tumor suppressive miRNAs using miRNA mimics could be promising approaches for cancer therapy.

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“…The EMT transcription factor SNAI1 represses transcription of the TS miRNA Let-7 in cancer. SNAI1 bind let-7 family promoters to inhibit miRNA transcription (27).…”

Section: Ts Mirna Promote Apoptosis In Cancermentioning

confidence: 99%

Tumor Suppressor miRNA in Cancer Cells and the Tumor Microenvironment: Mechanism of Deregulation and Clinical Implications

Otmani

Lewalle

2021

Front. Oncol.

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“…Analysis of a panel of patient-derived high-grade serous ovarian cancer cells revealed an inverse association between microRNA let-7 expression and the cancer stem cell phenotype, with low let-7 levels being associated with an epithelial phenotype [ 84 ]. This finding may be associated with a regulatory impact of the EMT-marker snail on let-7 [ 85 ]. One target of let-7d is c-Myc, an essential oncogenic transcription factor that is involved in tumor pathogenesis and frequently dysregulated in cancer [ 86 ].…”

Section: Let-7d and Ovarian Cancermentioning

confidence: 99%

The Role of microRNA Let-7d in Female Malignancies and Diseases of the Female Reproductive Tract

Santis¹,

Götte²

2021

IJMS

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microRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level. Let-7d is a microRNA of the conserved let-7 family that is dysregulated in female malignancies including breast cancer, ovarian cancer, endometrial cancer, and cervical cancer. Moreover, a dysregulation is observed in endometriosis and pregnancy-associated diseases such as preeclampsia and fetal growth restriction. Let-7d expression is regulated by cytokines and steroids, involving transcriptional regulation by OCT4, MYC and p53, as well as posttranscriptional regulation via LIN28 and ADAR. By downregulating a wide range of relevant mRNA targets, let-7d affects cellular processes that drive disease progression such as cell proliferation, apoptosis (resistance), angiogenesis and immune cell function. In an oncological context, let-7d has a tumor-suppressive function, although some of its functions are context-dependent. Notably, its expression is associated with improved therapeutic responses to chemotherapy in breast and ovarian cancer. Studies in mouse models have furthermore revealed important roles in uterine development and function, with implications for obstetric diseases. Apart from a possible utility as a diagnostic blood-based biomarker, pharmacological modulation of let-7d emerges as a promising therapeutic concept in a variety of female disease conditions.

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“…While the regulation of let-7 is incompletely understood, transcriptional, post-transcriptional, and epigenetic regulation are known to occur [ 30 ]. Factors that decrease levels of let-7 have also been shown to increase the stemness, invasiveness, and chemoresistance of cancer cells [ 31 , 32 , 33 ]. In our previous work, we demonstrated that patient-derived (PD) samples with low levels of let-7 correlate with increased self-renewal, pluripotency, and tumor burden [ 34 ].…”

Section: Introductionmentioning

confidence: 99%

Let-7i Reduces Aggressive Phenotype and Induces BRCAness in Ovarian Cancer Cells

Chirshev

Suzuki

Wang

et al. 2021

Cancers

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High-grade serous carcinoma of the ovary is a deadly gynecological cancer with poor long-term survival. Dysregulation of microRNAs has been shown to contribute to the formation of cancer stem cells (CSCs), an important part of oncogenesis and tumor progression. The let-7 family of microRNAs has previously been shown to regulate stemness and has tumor suppressive actions in a variety of cancers, including ovarian. Here, we demonstrate tumor suppressor actions of let-7i: repression of cancer cell stemness, inhibition of migration and invasion, and promotion of apoptosis, features important for cancer progression, relapse, and metastasis. Let-7i over-expression results in increased sensitivity to the PARP inhibitor olaparib in samples without BRCA mutations, consistent with induction of BRCAness phenotype. We also show that let-7i inhibits the expression of several factors involved in the homologous recombination repair (HRR) pathway, providing potential mechanisms by which the BRCAness phenotype could be induced. These actions of let-7i add to the rationale for use of this miRNA as a treatment for ovarian cancer patients, including those without mutations in the HRR pathway.

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The Epithelial–Mesenchymal Transcription Factor SNAI1 Represses Transcription of the Tumor Suppressor miRNA let-7 in Cancer

Cited by 19 publications

References 69 publications

Tumor Suppressor miRNA in Cancer Cells and the Tumor Microenvironment: Mechanism of Deregulation and Clinical Implications

Tumor Suppressor miRNA in Cancer Cells and the Tumor Microenvironment: Mechanism of Deregulation and Clinical Implications

The Role of microRNA Let-7d in Female Malignancies and Diseases of the Female Reproductive Tract

Let-7i Reduces Aggressive Phenotype and Induces BRCAness in Ovarian Cancer Cells

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