IGF-1R, a target of let-7b, mediates crosstalk between IRS-2/Akt and MAPK pathways to promote proliferation of oral squamous cell carcinoma

Gao, Ling; Wang, Xiaolong; Wang, Xiaofei; Zhang, Linmei; Cui, Qiang; Chang, Sue; Ren, Wenhao; Li, Shaoming; Yang, Yang; Tong, Dongdong; Chen, Cheng; Li, Zong-Fang; Song, Taek Lyul; Zhi, Kangkang; Huang, Chen

doi:10.18632/oncotarget.1812

Cited by 46 publications

(48 citation statements)

References 51 publications

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“…The results indicate that the tumor-inhibitory effect is not solely owing to downregulation of IRS2; other molecules regulated by miR-30a may also contribute to this phenotype. Recent research demonstrated that activated ERK could upregulate the expression of IRS2 (52). Thus, the connection between miR-30a, ERK, and IRS2 raises the possibility that miR-30a targets IRS2, both directly and indirectly.…”

Section: Discussionmentioning

confidence: 99%

Role of MicroRNA 30a Targeting Insulin Receptor Substrate 2 in Colorectal Tumorigenesis

Zhang

Tang

Qin

et al. 2015

Molecular and Cellular Biology

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d MicroRNAs (miRNAs) are dysregulated in many types of malignant diseases, including colorectal cancer. miRNA 30a (miR-30a) is a member of the miR-30 family and has been implicated in many types of cancers. In this study, we determined the expression of miR-30a in human colon cancer tissues and cell lines. miR-30a was found to be significantly downregulated in both the tissues and cell lines. Furthermore, overexpression of miR-30a inhibited, while silencing of miR-30a promoted, cell proliferation, migration, and invasion in vitro. Consistently, stable overexpression of miR-30a suppressed the growth of colon cancer cell xenografts in vivo. Moreover, bioinformatic algorithms and luciferase reporter assays revealed that insulin receptor substrate 2 (IRS2) is a direct target of miR-30a. Further functional studies suggested that repression of IRS2 by miR-30a partially mediated the tumor suppressor effect of miR-30a. In addition, miR-30a inhibited constitutive phosphorylation of Akt by targeting IRS2. Additionally, clinicopathological analysis indicated that miR-30a has an inverse correlation with the staging in patients with colon cancer. Taken together, our study provides the first evidence that miR-30a suppressed colon cancer cell growth through inhibition of IRS2. Thus, miR-30a might serve as a promising therapeutic strategy for colon cancer treatment. Colorectal cancer (CRC) is the third most common cancer in males and females, with an estimated 142,820 new cases and 50,830 deaths in the United States in 2013. The overall CRC incidence is 5% in the general population, and the 5-year survival rate ranges from 40% to 60% (1). Despite the improvement of currently available treatment strategies, including surgical resection, radiotherapy, and chemotherapy, the survival rate of patients with CRC has changed little over the past 10 years. Almost 50% of CRC patients will die of the disease, mainly due to metastasis to the liver. Thus, it is imperative to achieve earlier diagnosis and better tailoring of treatments to improve CRC outcomes.MicroRNAs (miRNAs) are a family of endogenous small noncoding RNAs that regulate gene expression via the sequence-specific base pairing on the 3= untranslated regions (3= UTRs) of target mRNAs, resulting in mRNA cleavage or translation inhibition (2). More than 30% of the protein-coding genes are controlled by miRNAs, as indicated by bioinformatics predictions. miRNAs are involved in a plethora of biological processes, such as proliferation, migration, invasion, and apoptosis (3, 4). In recent years, miRNAs have been recognized as critical regulators in development and progression of cancer, including CRC (5-8).miRNA 30a (miR-30a) is a member of the miR-30 family, which consists of six distinct mature miRNA sequences: miR-30a/ miR-30c-2, miR-30d/miR-30b, and miR-30e/miR-30c-1 (9). There is considerable evidence suggesting that the dysregulation of miR-30a is correlated with several types of malignant tumors, including breast cancer, lung cancer, thyroid cancer, gastric cancer, and leuke...

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Section: Discussionmentioning

confidence: 99%

Role of MicroRNA 30a Targeting Insulin Receptor Substrate 2 in Colorectal Tumorigenesis

Zhang

Tang

Qin

et al. 2015

Molecular and Cellular Biology

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“…Primary cathepsin B antibody was obtained from D. J. Buttle, University of Sheffield, UK (Buttle et al, 1988). Antibodies against the following proteins were purchased from manufacturers as listed below: actin (Sigma-Aldrich, St. Louis, MO) (Zhou et al, 2005), calnexin (Millipore, Carrigtwohill, Ireland) (Methner and Mayfield, 2010), EGF receptor (Cell Signaling Technologies, Danvers, MA) (Kawahara et al, 2010), Grb-2 (Cell Signaling Technologies) (Benitez et al, 2011), IGF-1R (Cell Signaling) (Michels et al, 2013), IRS-2 (Cell Signaling) (Gao et al, 2014), Lamp-1 (Cell Signaling), LC-3B (Cell Signaling) (Tong et al, 2012), MAPK (Cell Signaling) (Michels et al, 2013), Akt (Cell Signaling), p-IGF-1Rb (Cell Signaling), p-MAPK (Cell Signaling), p-Akt (Cell Signaling) (Michels et al, 2013), p-Shc A (Cell Signaling) (Krall et al, 2011), RAS (Cell Signaling), Shc A (Cell Signaling), N-Shc (BD Biosciences, San Jose, CA) (Tarr et al, 2002). The secondary goat fluor-568 anti-rabbit antibody was from Invitrogen.…”

Section: Methodsmentioning

confidence: 99%

Cathepsin Inhibition Prevents Autophagic Protein Turnover and Downregulates Insulin Growth Factor-1 Receptor-Mediated Signaling in Neuroblastoma

Soori

Mason

2015

Journal of Pharmacology and Experimental Therapeutics

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Inhibition of the major lysosomal proteases, cathepsins B, D, and L, impairs growth of several cell types but leads to apoptosis in neuroblastoma. The goal of this study was to examine the mechanisms by which enzyme inhibition could cause cell death. Cathepsin inhibition caused cellular accumulation of fragments of the insulin growth factor 1 (IGF-1) receptor. The fragments were located in dense organelles that were characterized as autophagosomes. This novel discovery provides the first clear link between lysosomal function, autophagy, and IGF-1-mediated cell proliferation. A more in-depth analysis of the IGF1 signaling pathway revealed that the mitogen-activated protein kinase (MAPK) cell-proliferation pathway was impaired in inhibitor treated cells, whereas the Akt cell survival pathway remained functional. Shc, an adapter protein that transmits IGF-1 signaling through the MAPK pathway, was sequestered in autophagosomes; whereas IRS-2, an adapter protein that transmits IGF-1 signaling through the Akt pathway, was unaffected by cathepsin inhibition. Furthermore, Shc was sequestered in autophagosomes as its active form, indicating that autophagy is a key mechanism for downregulating IGF-1-induced cell proliferation. Cathepsin inhibition had a greater effect on autophagic sequestration of the neuronal specific adapter protein, Shc-C, than ubiquitously expressed Shc-A, providing mechanistic support for the enhanced sensitivity of neuronally derived tumor cells. We also observed impaired activation of MAPK by epidermal growth factor treatment in inhibitor-treated cells. The Shc adapter proteins are central to transducing proliferation signaling by a range of receptor tyrosine kinases; consequently, cathepsin inhibition may become an important therapeutic approach for treating neuroblastoma and other tumors of neuronal origin.

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“…miRNAs are small, noncoding RNAs of 19-25 nucleotides, which regulate physiologic process or pathogenesis by targeting the mRNA to cause transcriptional repression or mRNA degradation (6,7). A number of disruptions in miRNA-target gene regulatory axes in OSCC have been discovered (8)(9)(10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-211 Enhances the Oncogenicity of Carcinogen-Induced Oral Carcinoma by Repressing TCF12 and Increasing Antioxidant Activity

Chen¹,

et al. 2016

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miR-211 expression in human oral squamous cell carcinoma (OSCC) has been implicated in poor patient survival. To investigate the oncogenic roles of miR-211, we generated K14-EGFPmiR-211 transgenic mice tagged with GFP. Induction of oral carcinogenesis in transgenic mice using 4-nitroquinoline 1-oxide (4NQO) resulted in more extensive and severe tongue tumorigenesis compared with control animals. We found that 4NQO and arecoline upregulated miR-211 expression in OSCC cells. In silico and experimental evidence further revealed that miR-211 directly targeted transcription factor 12 (TCF12), which mediated suppressor activities in OSCC cells and was drastically downregulated in tumor tissues. We used GeneChip analysis and bioinformatic algorithms to identify transcriptional targets of TCF12 and confirmed through reporter and ChIP assays that family with sequence similarity 213, member A (FAM213A), a peroxiredoxin-like antioxidative protein, was repressed transcriptionally by TCF12. FAM213A silencing in OSCC cells diminished oncogenic activity, reduced the ALDH1-positive cell population, and increased reactive oxygen species. TCF12 and FAM213A expression was correlated inversely in head and neck carcinoma samples according to The Cancer Genome Atlas. OSCC patients bearing tumors with high FAM213A expression tended to have worse survival. Furthermore, 4NQO treatment downregulated TCF12 and upregulated FAM213A by modulating miR-211 both in vitro and in vivo. Overall, our findings develop a mouse model that recapitulates the molecular and histopathologic alterations of human OSCC pathogenesis and highlight a new miRNA-mediated oncogenic mechanism. Cancer Res; 76(16); 4872-86. Ó2016 AACR.

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IGF-1R, a target of let-7b, mediates crosstalk between IRS-2/Akt and MAPK pathways to promote proliferation of oral squamous cell carcinoma

Cited by 46 publications

References 51 publications

Role of MicroRNA 30a Targeting Insulin Receptor Substrate 2 in Colorectal Tumorigenesis

Role of MicroRNA 30a Targeting Insulin Receptor Substrate 2 in Colorectal Tumorigenesis

Cathepsin Inhibition Prevents Autophagic Protein Turnover and Downregulates Insulin Growth Factor-1 Receptor-Mediated Signaling in Neuroblastoma

MicroRNA-211 Enhances the Oncogenicity of Carcinogen-Induced Oral Carcinoma by Repressing TCF12 and Increasing Antioxidant Activity

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