IRS4 promotes the progression of non-small cell lung cancer and confers resistance to EGFR-TKI through the activation of PI3K/Akt and Ras-MAPK pathways

Hao, Peiqi; Huang, Ying; Peng, Jun; Yu, Jiaojiao; Guo, Xuewu; Bao, Fan; Dian, Ziqin; An, Su; Xu, Tian‐Rui

doi:10.1016/j.yexcr.2021.112615

Cited by 16 publications

(14 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To our knowledge, this is the first study demonstrating a possible pathophysiological role of this marker in these tumors. IRS-4 is an adaptor protein acting as a constitutive activator of critical cell transduction pathways in cancer, leading to the activation of the PI3K/Akt pathway collaborating with the actions of the human epidermal growth factor receptor 2 (HER2) [13]. HER2 is a central receptor involved in BC development and stratification.…”

Section: Discussionmentioning

confidence: 99%

“…Insulin receptor substrate 4 (IRS-4) is a relevant molecule altered in different types of malignancies like BC. It seems that this molecule promotes tumoral proliferation and therapy resistance due to the alteration of different molecular pathways [13][14][15]. Furthermore, previous studies have found that an overexpression of this component is frequently related to a poorer prognosis [16].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Patients with Invasive Lobular Carcinoma Show a Significant Increase in IRS-4 Expression Compared to Infiltrative Ductal Carcinoma—A Histopathological Study

et al. 2022

View full text Add to dashboard Cite

Background and Objectives: Breast cancer (BC) is the first diagnosed type of cancer and the second leading cause of cancer-related mortality in women. In addition, despite the improvement in treatment and survival in these patients, the global prevalence and incidence of this cancer are rising, and its mortality may be different according to the histological subtype. Invasive lobular carcinoma (ILC) is less common but entails a poorer prognosis than infiltrative ductal carcinoma (IDC), exhibiting a different clinical and histopathological profile. Deepening study on the molecular profile of both types of cancer may be of great aid to understand the carcinogenesis and progression of BC. In this sense, the aim of the present study was to explore the histological expression of Insulin receptor substrate 4 (IRS-4), cyclooxygenase 2 (COX-2), Cyclin D1 and retinoblastoma protein 1 (Rb1) in patients with ILC and IDC. Patients and Methods: Thus, breast tissue samples from 45 patients with ILC and from 45 subjects with IDC were analyzed in our study. Results: Interestingly, we observed that IRS-4, COX-2, Rb1 and Cyclin D1 were overexpressed in patients with ILC in comparison to IDC. Conclusions: These results may indicate a differential molecular profile between both types of tumors, which may explain the clinical differences among ILC and IDC. Further studies are warranted in order to shed light onto the molecular and translational implications of these components, also aiding to develop a possible targeted therapy to improve the clinical management of these patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Patients with Invasive Lobular Carcinoma Show a Significant Increase in IRS-4 Expression Compared to Infiltrative Ductal Carcinoma—A Histopathological Study

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Moreover, we observed an increase of metalloproteinase 2 (MMP-2) production in IRS-4 depleted cells. A very recent study shows that decreases in IRS-4 levels causes a reduction of E-cadherin, another sign of EMT activation [ 11 ]. Moreover, IRS-4-depleted cells responded more efficiently than control cells to the chemotactic stimuli (collagen type I and EGF).…”

Section: Discussionmentioning

confidence: 99%

“…Other studies have found IRS-4 expression is significantly low in normal tissues [ 3 , 6 ]. In contrast, IRS-4 has been shown to be overexpressed in benign proliferative lesions such as uterine leiomyomas [ 7 ] and subungual exostosis [ 8 ], as well as in malignant diseases such as breast cancer [ 9 ], leukemia [ 10 ], lung cancer [ 4 , 11 ], and colorectal cancer [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Possible Role of IRS-4 in the Origin of Multifocal Hepatocellular Carcinoma

Guijarro

Sanmartín-Salinas

Pérez-Cuevas

et al. 2021

Cancers

View full text Add to dashboard Cite

New evidence suggests that insulin receptor substrate 4 (IRS-4) may play an important role in the promotion of tumoral growth. In this investigation, we have evaluated the role of IRS-4 in a pilot study performed on patients with liver cancer. We used immunohistochemistry to examine IRS-4 expression in biopsies of tumoral tissue from a cohort of 31 patient suffering of hepatocellular carcinoma (HCC). We simultaneously analyzed the expression of the cancer biomarkers PCNA, Ki-67, and pH3 in the same tissue samples. The in vitro analysis was conducted by studying the behavior of HepG2 cells following IRS-4 overexpression/silencing. IRS-4 was expressed mainly in the nuclei of tumoral cells from HCC patients. In contrast, in healthy cells involved in portal triads, canaliculi, and parenchymal tissue, IRS-4 was observed in the cytosol and the membrane. Nuclear IRS-4 in the tumoral region was found in 69.9 ± 3.2%, whereas in the surrounding healthy hepatocytes, nuclear IRS-4 was rarely observed. The percentage of tumoral cells that exhibited nuclear PCNA and Ki-67 were 52.1 ± 7%, 6.1 ± 1.1% and 1.3 ± 0.2%, respectively. Furthermore, we observed a significant positive linear correlation between nuclear IRS-4 and PCNA (r = 0.989; p < 0.001). However, when we correlated the nuclear expression of IRS-4 and Ki-67, we observed a significant positive curvilinear correlation (r = 0.758; p < 0.010). This allowed us to define two populations, (IRS-4 + Ki-67 ≤ 69%) and (IRS-4 + Ki-67 > 70%). The population with lower levels of IRS-4 and Ki-67 had a higher risk of suffering from multifocal liver cancer (OR = 16.66; CI = 1.68–164.8 (95%); p < 0.05). Immunoblot analyses showed that IRS-4 in normal human liver biopsies was lower than in HepG2, Huh7, and Chang cells. Treatment of HepG2 with IGF-1 and EGF induced IRS-4 translocation to the nucleus. Regulation of IRS-4 levels via HepG2 transfection experiments revealed the protein’s role in proliferation, cell migration, and cell-collagen adhesion. Nuclear IRS-4 is increased in the tumoral region of HCC. IRS-4 and Ki-67 levels are significantly correlated with the presence of multifocal HCC. Moreover, upregulation of IRS-4 in HepG2 cells induced proliferation by a β-catenin/Rb/cyclin D mechanism, whereas downregulation of IRS-4 caused a loss in cellular polarity and in its adherence to collagen as well as a gain in migratory and invasive capacities, probably via an integrin α2 and focal adhesion cascade (FAK) mechanism.

show abstract

“…Zhou et al found that PI3K/Akt signaling pathway was suppressed by miR-200c to strengthen the sensitivity of drug-resistant NSCLC cells to gefitinib ( 13 ). Hao et al demonstrated that IRS4 conferred therapy resistance in lung cancer cells through activating PI3K/Akt signaling ( 14 ). These studies collectively indicate PI3K/Akt signaling pathway may be a promising target of overcoming the gefitinib resistance in NSCLC.…”

Section: Introductionmentioning

confidence: 99%

Sensitization of Non-Small Cell Lung Cancer Cells to Gefitinib and Reversal of Epithelial–Mesenchymal Transition by Aloe-Emodin Via PI3K/Akt/TWIS1 Signal Blockage

et al. 2022

View full text Add to dashboard Cite

ObjectiveTo explore the impacts of AE (aloe-emodin) in gefitinib-resistant NSCLC (non-small cell lung cancer) cells and the corresponding mechanism.MethodsPC9 and PC9-GR cells were cultured and treated by gefitinib, AE, or the combination of the two drugs. Then, viability, apoptosis, migration and invasion of cells were investigated using CCK-8, TUNEL, wound healing assay, and transwell assay, respectively. Female BALB/c nude mice were employed for the establishment of xenograft tumor models to examine the role of AE in tumor growth.ResultsPC9-GR cells showed reduced apoptosis and enhanced cell viability, migration and invasion upon treatment by gefitinib, compared with PC9 cells. E-cahherin in PC9-GR cells was down-regulated, while Vimentin, Snail2 (or Slug) and Twist1 in PC9-GR cells were up-regulated, compared with PC9 cells. Meanwhile, treatment by a combination of gefitinib and AE significantly strengthened apoptosis of PC9-GR cells, while attenuated their migration and invasion, compared with the control group or treatment by gefitinib or AE alone. WB results showed that AE could reverse EMT and activation of PI3K/AKT signalling pathway in PC9-GR cells. In vivo experiments showed that tumor growth and EMT of PC9-GR cells were dramatically repressed after treatment by a combination of AE and gefitinib. Additionally, the use of SC97 (a PI3K/Akt pathway activator) could counteract the effects of AE in gefitinib-resistant PC9 cells.ConclusionsAE could enhance the gefitinib sensitivity of PC9-GR cells and reverse EMT by blocking PI3K/Akt/TWIS1 signal pathway.

show abstract

IRS4 promotes the progression of non-small cell lung cancer and confers resistance to EGFR-TKI through the activation of PI3K/Akt and Ras-MAPK pathways

Cited by 16 publications

References 42 publications

Patients with Invasive Lobular Carcinoma Show a Significant Increase in IRS-4 Expression Compared to Infiltrative Ductal Carcinoma—A Histopathological Study

Patients with Invasive Lobular Carcinoma Show a Significant Increase in IRS-4 Expression Compared to Infiltrative Ductal Carcinoma—A Histopathological Study

Possible Role of IRS-4 in the Origin of Multifocal Hepatocellular Carcinoma

Sensitization of Non-Small Cell Lung Cancer Cells to Gefitinib and Reversal of Epithelial–Mesenchymal Transition by Aloe-Emodin Via PI3K/Akt/TWIS1 Signal Blockage

Contact Info

Product

Resources

About