Insulin receptor substrate 2: a bridge between Hippo and AKT pathways

Jeong, Sunhye; Lim, Dae‐Sik

doi:10.5483/bmbrep.2018.51.5.095

Cited by 15 publications

(9 citation statements)

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“…. IRS2 has previously been reported to participate in regulation of the PI3K/Akt pathway (28)(29)(30). Therefore, it was hypothesized that miR-766 may target IRS2 to inhibit the activation of PI3K/Akt signaling in PTC cells.…”

Section: Mir-766 Suppresses Activation Of the Pi3k/akt Pathway In Ptcmentioning

confidence: 99%

MicroRNA‑766 inhibits papillary thyroid cancer progression by directly targeting insulin receptor substrate 2 and regulating the PI3K/Akt pathway

Zhao

Chen

et al. 2018

Int J Oncol

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MicroRNAs (miRNAs/miRs) are widely dysregulated in papillary thyroid cancer (PTC). Dysregulated miRNAs, together with their target genes, comprise a complex network that has been implicated in the regulation of PTC pathogenesis. Further knowledge of the functional roles of aberrantly expressed miRNAs in PTC, and the underlying molecular mechanisms, may assist in the identification of novel therapeutic targets. miR-766 has been well studied in human cancer; however, the expression status, specific roles and regulatory mechanisms of miR-766 in PTC remain unclear. The present study aimed to detect miR-766 expression in PTC tissues and cell lines, to explore the biological roles of miR-766 in the malignant biological behaviors of PTC cells, and to determine the underlying mechanism of action of miR-766 in PTC cells. The results revealed that miR-766 was downregulated in PTC tissues and cell lines, and its downregulation was strongly associated with TNM stage and lymph node metastasis. Overexpression of miR-766 inhibited PTC cell proliferation, colony formation, migration and invasion, promoted cell apoptosis and reduced tumor growth in vivo. Mechanistically, insulin receptor substrate 2 (IRS2) was identified as a direct target of miR-766 in PTC cells. IRS2 was upregulated in PTC tissues, and this was inversely correlated with miR-766 expression. Inhibition of IRS2 simulated the tumor suppressor activity of miR-766 in PTC cells. Restoration of IRS2 expression negated the tumor-suppressing effects of miR-766 overexpression on PTC cells. Notably, miR-766 directly targeted IRS2 to inhibit activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway in PTC cells in vitro and in vivo. Overall, these findings indicated that miR-766 may inhibit the malignant biological behaviors of PTC cells by directly targeting IRS2 and regulating the PI3K/Akt pathway, thus suggesting that this miRNA may be a promising therapeutic target for PTC.

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Section: Mir-766 Suppresses Activation Of the Pi3k/akt Pathway In Ptcmentioning

confidence: 99%

MicroRNA‑766 inhibits papillary thyroid cancer progression by directly targeting insulin receptor substrate 2 and regulating the PI3K/Akt pathway

Zhao

Chen

et al. 2018

Int J Oncol

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“…LncARSR regulating AKT-related pathway was also exhibited in another study [17], in which lncARSR activates the PI3K/AKT pathway by promoting PTEN expression. Furthermore, Jeong et al reported that Hippo-YAP/TAZ connecting with activation of IRS2/AKT plays a role in the development of NAFLD [22]. The previous study showed NAFLD was characterized by dysregulation of lipid metabolism in the liver, and less-differentiated HepG2 cells could suppress lipid accumulation [23].…”

Section: Discussionmentioning

confidence: 99%

Long noncoding RNA lncARSR promotes nonalcoholic fatty liver disease and hepatocellular carcinoma by promoting YAP1 and activating the IRS2/AKT pathway

Chi

Gong

et al. 2020

J Transl Med

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Background Nonalcoholic fatty liver disease (NAFLD) is the main cause for hepatocellular carcinoma (HCC). This study was intended to identify the function of long non-coding RNA (lncRNA) lncARSR in NAFLD and its role in human HCC cells (HepG2) proliferation and invasion. Methods LncARSR expression was detected both in high fatty acid-treated HepG2 cells and NAFLD mouse model. After gain- and loss-of-function approaches in high fatty acid-treated HepG2 cells and NAFLD mice, lipid accumulation in livers from NAFLD mice and high fatty acid-treated cells was determined by H&E staining, Oil Red-O staining or Nile Red staining respectively. Expression of YAP1, adipogenesis- (Fasn, Scd1 and GPA) and IRS2/AKT pathway-related genes was measured. Cell proliferation was monitored by MTT and soft-agar colony formation assays, cell cycle was analyzed by flow cytometry, and cell invasion was examined by transwell assay. The tumor weight and volume were then measured through in vivo xenograft tumor model after silencing lncARSR. Results LncARSR was highly expressed in high fatty diet (HFD)-fed mice and high fatty acid-treated HepG2 cells. LncARSR was observed to bind to YAP1, which inhibited phosphorylation nuclear translocation. LncARSR activated the IRS2/AKT pathway by reducing YAP1 phosphorylation, and further increased lipid accumulation, cell proliferation, invasion and cell cycle. Silencing lncARSR in HFD-fed mice alleviated NAFLD by regulating YAP1/IRS2/AKT axis. Conclusion Silencing lncARSR suppressed the IRS2/AKT pathway, consequently reducing HCC cell proliferation and invasion and inhibiting lipid accumulation in NAFLD mice by downregulating YAP1, which suggests a clinical application in treating NAFLD.

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“…In the previous reports, evidence suggested that PDK-1 can mediate Hippo–YAP pathway, moreover, YAP regulates IRS2 pathway [25,26]. In the present study, we observed that PDK-1 silence suppressed YAP and IRS2 protein expression both in H1299 cells and A549 cells (Figure 4A,B); also we demonstrated that YAP overexpression markedly increased IRS2 protein expression compared with PDK-1 silence group (Figure 4C), these results indicated that PDK-1 knockdown impeded IRS2 expression through inhibiting YAP expression.…”

Section: Resultsmentioning

confidence: 99%

PDK-1 mediated Hippo–YAP–IRS2 signaling pathway and involved in the apoptosis of non-small cell lung cancer cells

et al. 2019

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Pyruvate dehydrogenase kinase-1 (PDK-1), a gatekeeper enzyme, was involved in cancer progression, such as tumor angiogenesis, cell survival, and growth. Recent evidence indicated that PDK-1 may be involved in lung cancer, however, the function and underlying mechanism of PDK-1 is remaining unclear. In the present study, our aim was to investigate the role and mechanisms of PDK-1 in human non-small cell lung cancer (NSCLC) cells. We first observed that PDK-1 was highly expressed in NSCLC cell lines. PDK-1 silence resulted in the inhibition of NSCLC cell survival. Also, cell apoptosis and caspase-3 activity were increased by PDK-1 knockdown in H1299 and A549 cells. Attenuation of PDK-1 expression blocked YAP and insulin receptor substrate 2 (IRS2) expression, and PDK-1 silence suppressed IRS2 expression dependent on Hippo–YAP signaling pathway. Moreover, further studies confirmed that YAP or IRS2 overexpression reversed the action of PDK-1 in NSCLC cells. In conclusion, our findings indicate that PDK1/Hippo–YAP/IRS2 signaling pathway plays a critical role in NSCLC cell survival and apoptosis.

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Insulin receptor substrate 2: a bridge between Hippo and AKT pathways

Cited by 15 publications

References 0 publications

MicroRNA‑766 inhibits papillary thyroid cancer progression by directly targeting insulin receptor substrate 2 and regulating the PI3K/Akt pathway

MicroRNA‑766 inhibits papillary thyroid cancer progression by directly targeting insulin receptor substrate 2 and regulating the PI3K/Akt pathway

Long noncoding RNA lncARSR promotes nonalcoholic fatty liver disease and hepatocellular carcinoma by promoting YAP1 and activating the IRS2/AKT pathway

PDK-1 mediated Hippo–YAP–IRS2 signaling pathway and involved in the apoptosis of non-small cell lung cancer cells

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