<scp><i>IRS2</i></scp> is a candidate driver oncogene on 13q34 in colorectal cancer

Day, Emerson; Poulogiannis, George; McCaughan, Frank; Mulholland, Shani A.; Arends, Mark J.; Ibrahim, Ashraf E.K.; Dear, Paul H.

doi:10.1111/iep.12021

Cited by 45 publications

(45 citation statements)

References 46 publications

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“…The fourth IRS protein, IRS3, has been identified in rodents but not in humans (37,38). Over the past decade, there has been a considerable amount of evidence to support an oncogenic role of IRS2 in many types of cancers including CRC (39)(40)(41)(42). IRS2 is located in the 13q34 region, which is frequently gained in CRC, with a prevalence of up to 85% as reported in the literature (43,44).…”

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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“…Similar to IRS-1, IRS-2 has also been implicated in promoting tumor cell survival and proliferation [28]. Cumulative evidence suggests that IRS-2 is overexpressed in cancers, such as pancreatic adenocarcinoma [29], breast cancer [30], and colorectal cancer [31]. It is identified as a positive regulator of cell proliferation in breast cancer [32,33] and oral squamous cell carcinoma [34], and as a driver oncogene in colorectal cancer [31].…”

Section: Discussionmentioning

confidence: 99%

“…Cumulative evidence suggests that IRS-2 is overexpressed in cancers, such as pancreatic adenocarcinoma [29], breast cancer [30], and colorectal cancer [31]. It is identified as a positive regulator of cell proliferation in breast cancer [32,33] and oral squamous cell carcinoma [34], and as a driver oncogene in colorectal cancer [31]. Deletion of IRS-2 has no impact on tumor initiation, but it does suppress tumor growth and progression to invasive disease [35].…”

Section: Discussionmentioning

confidence: 99%

miR-106a* inhibits the proliferation of renal carcinoma cells by targeting IRS-2

Zhang

et al. 2015

Tumor Biol.

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MicroRNAs play critical roles in the development and progression of human cancers. Although it has been reported that miR-106a* is downregulated in follicular lymphoma, its role in renal cell carcinoma (RCC) remains unknown. This study investigated the expression and role of miR-106a* in human RCC. Our results showed that the miR-106a* expression decreased dramatically in clinical RCC tissues and cell lines. In vitro, overexpression of miR-106a* suppressed RCC cell proliferation and S/G2 transition, whereas inhibition of miR-106a* promoted cell proliferation and S/G2 transition. It was also found that miR-106a* expression was inversely correlated with the expression of insulin receptor substrate 2 (IRS-2). IRS-2 was determined to be a direct target of miR-106a* by a luciferase reporter assay. Importantly, silencing IRS-2 resulted in the same biologic effects as those of miR-106a* overexpression in RCC cells, including inhibition of RCC cell proliferation and triggering of S/G2 cell cycle arrest with inhibition of the PI3K/Akt signaling pathway. These results indicate that miR-106a* affects RCC progression by targeting IRS-2 with suppression of the PI3K/Akt signaling pathway in RCC cells. The findings suggest miR-106a* as a novel strategy for RCC treatment.

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“…Importantly, IRS2 overexpression is sufficient to activate PI3K/AKT signaling in cell line models [163].…”

Section: Regulation Of the Pi3k Transcriptome And Proteome In Colorecmentioning

confidence: 99%

Portrait of the PI3K/AKT pathway in colorectal cancer

Danielsen¹,

Eide²,

Nesbakken³

et al. 2015

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

233

200

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IRS2 is a candidate driver oncogene on 13q34 in colorectal cancer

Cited by 45 publications

References 46 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

miR-106a* inhibits the proliferation of renal carcinoma cells by targeting IRS-2

Portrait of the PI3K/AKT pathway in colorectal cancer

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