Tumor suppressor miR-375 regulates MYC expression via repression of CIP2A coding sequence through multiple miRNA–mRNA interactions

Jung, Hyun Min; Patel, Rushi S.; Phillips, Brittany L.; Wang, Hai; Cohen, Donald M.; Reinhold, William C.; Chang, Lung‐Ji; Yang, Lijun; Chan, Edward K. L.

doi:10.1091/mbc.e12-12-0891

Cited by 84 publications

(82 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Jung and his colleagues showed that four anti-cancer drugs (doxorubicin, 5-fluorouracil, trichostatin A and etoposide) could induce the expression of tumor suppressor miR-375 in tongue cancer [24]. This research group also testified that underexpression of tumor suppressor miR-375 contributes to promoting cancerous phenotypes by inducing uncontrolled CIP2A expression and extended stability of MYC [25]. Meanwhile, they showed that miR-375 activates p21 and suppresses telomerase activity by coordinately regulating HPV E6/E7, E6AP, CIP2A, and 14-3-3ζ [26].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-375 Inhibits Growth and Enhances Radiosensitivity in Oral Squamous Cell Carcinoma by Targeting Insulin Like Growth Factor 1 Receptor

Zhang

Hou

et al. 2017

Cell Physiol Biochem

View full text Add to dashboard Cite

Background: MicroRNAs (miRNAs) have emerged as key players in various human biological processes, including tumorigenesis. Here, we investigated the roles of miR-375 in the pathogenesis of oral squamous cell carcinoma (OSCC). Methods: We performed quantitative real-time PCR (qRT-PCR) to detect miR-375 expression in OSCC tissues and corresponding normal oral epithelial tissues and analyze the correlation of miR-375 expression with OSCC metastasis and patient’s survival. Then, the effects of miR-375 expression on proliferation, cell cycle, apoptosis and radiosensitivity in OSCC cells were determined by using MTT, flow cytometry and clonogenic survival assays. A dual-luciferase reporter assay was performed to test whether miR-375 binds to the 3’-untranslated region (3’-UTR) of target mRNA. Results: The expression level of miR-375 in OSCC tissues was significantly lower than that in normal oral epithelial tissues, and low miR-375 expression was correlated with higher incidence of lymph node metastasis and poor survival of OSCC patients. Upregulation of miR-375 significantly inhibits growth, induces cell cycle arrest in G₀/G₁ phase, increases apoptosis and enhances radiosensitivity in OSCC cells. Analysis of luciferase activity demonstrated that miR-375 binds to the 3’-UTR of insulin like growth factor 1 receptor (IGF-1R). Small interfering RNA (shRNA)-mediated IGF-1R knockdown mimics the effects of miR-375 upregulation, while overexpression of IGF-1R partially reverses those effects in OSCC cells. Conclusion: It was obviously demonstrated that miRNA-375 inhibits growth and enhances radiosensitivity in OSCC cells by targeting IGF-1R, suggesting that miR-375 may be a potential therapeutic target for OSCC patients.

show abstract

Section: Discussionmentioning

confidence: 99%

MicroRNA-375 Inhibits Growth and Enhances Radiosensitivity in Oral Squamous Cell Carcinoma by Targeting Insulin Like Growth Factor 1 Receptor

Zhang

Hou

et al. 2017

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…At first glance this result seems to vary from our observations. However, several studies have reported that miR-375 acts not as a positive regulator of cell proliferation but rather as a negative modulator (24,(34)(35)(36). At least two scenarios could account for this apparent divergence.…”

Section: Discussionmentioning

confidence: 99%

Maternal Protein Restriction Leads to Pancreatic Failure in Offspring: Role of Misexpressed MicroRNA-375

et al. 2014

View full text Add to dashboard Cite

The intrauterine environment of the fetus is a preeminent actor in long-term health. Indeed, mounting evidence shows that maternal malnutrition increases the risk of type 2 diabetes (T2D) in progeny. Although the consequences of a disturbed prenatal environment on the development of the pancreas are known, the underlying mechanisms are poorly defined. In rats, restriction of protein during gestation alters the development of the endocrine pancreas and favors the occurrence of T2D later in life. Here we evaluate the potential role of perturbed microRNA (miRNA) expression in the decreased b-cell mass and insulin secretion characterizing progeny of pregnant dams fed a low-protein (LP) diet. miRNA profiling shows increased expression of several miRNAs, including miR-375, in the pancreas of fetuses of mothers fed an LP diet. The expression of miR-375 remains augmented in neoformed islets derived from fetuses and in islets from adult (3-month-old) progeny of mothers fed an LP diet. miR-375 regulates the proliferation and insulin secretion of dissociated islet cells, contributing to the reduced b-cell mass and function of progeny of mothers fed an LP diet. Remarkably, miR-375 normalization in LP-derived islet cells restores b-cell proliferation and insulin secretion. Our findings suggest the existence of a developmental memory in islets that registers intrauterine protein restriction. Hence, pancreatic failure after in utero malnutrition could result from transgenerational transmission of miRNA misexpression in b-cells.

show abstract

“…[33][34][35] CIP2A stabilizes MYC through its inhibitory effect on PPP2. Immunoblot for CIP2A in ctrl and LAMP2A (-) cells with or without transduction with wild-type MYC (Fig.…”

Section: Cma Control Of Myc Accumulation Is Dependent On Myc Phosphormentioning

confidence: 99%

Chaperone-mediated autophagy prevents cellular transformation by regulating MYC proteasomal degradation

2017

View full text Add to dashboard Cite

Chaperone-mediated autophagy (CMA), a selective form of protein lysosomal degradation, is maximally activated in stress situations to ensure maintenance of cellular homeostasis. CMA activity decreases with age and in several human chronic disorders, but in contrast, in most cancer cells, CMA is upregulated and required for tumor growth. However, the role of CMA in malignant transformation remains unknown. In this study, we demonstrate that CMA inhibition in fibroblasts augments the efficiency of MYC/c-Mycdriven cellular transformation. CMA blockage contributes to the increase of total and nuclear MYC, leading to enhancement of cell proliferation and colony formation. Impaired CMA functionality accentuates tumorigenesis-related metabolic changes observed upon MYC-transformation. Although not a direct CMA substrate, we have found that CMA regulates cellular MYC levels by controlling its proteasomal degradation. CMA promotes MYC ubiquitination and degradation by regulating the degradation of C330027C09Rik/KIAA1524/CIP2A (referred to hereafter as CIP2A), responsible for MYC stabilization. Ubiquitination and proteasomal degradation of MYC requires dephosphorylation at Ser62, and CIP2A inhibits the phosphatase responsible for this dephosphorylation. Failure to degrade CIP2A upon CMA blockage leads to increased levels of phosphorylated MYC (Ser62) and to stabilization of this oncogene. We demonstrate that this phosphorylation is essential for the CMA-mediated effect, since specific mutation of this site (Ser62 to Ala62) is enough to normalize MYC levels in CMA-incompetent cells. Altogether these data demonstrate that CMA mitigates MYC oncogenic activity by promoting its proteasomal degradation and reveal a novel tumor suppressive role for CMA in nontumorigenic cells.

show abstract

Tumor suppressor miR-375 regulates MYC expression via repression of CIP2A coding sequence through multiple miRNA–mRNA interactions

Cited by 84 publications

References 70 publications

MicroRNA-375 Inhibits Growth and Enhances Radiosensitivity in Oral Squamous Cell Carcinoma by Targeting Insulin Like Growth Factor 1 Receptor

MicroRNA-375 Inhibits Growth and Enhances Radiosensitivity in Oral Squamous Cell Carcinoma by Targeting Insulin Like Growth Factor 1 Receptor

Maternal Protein Restriction Leads to Pancreatic Failure in Offspring: Role of Misexpressed MicroRNA-375

Chaperone-mediated autophagy prevents cellular transformation by regulating MYC proteasomal degradation

Contact Info

Product

Resources

About