Overexpressed ITGA2 contributes to paclitaxel resistance by ovarian cancer cells through the activation of the AKT/FoxO1 pathway

Ma, Linlin; Sun, Yan; Li, Dan; Li, Hansong; Jin, Xin; Ren, Dianyun

doi:10.18632/aging.102954

Cited by 39 publications

(24 citation statements)

References 42 publications

(46 reference statements)

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“…In regards to ovarian cancer, a recent study demonstrated that ovarian cancer cells with elevated ITGA2 led to poor prognosis and survival. Overexpression of ITGA2 promoted in vitro cancer cell aggressiveness and in vivo tumor growth through regulation of the phosphorylation of forkhead box O1 (FoxO1) and AKT phosphorylation, which provided the mechanism for ITGA2-mediated paclitaxel-resistance in ovarian cancer ( Ma et al, 2020 ). However, it remains uncertain how ITGA2 regulates AKT/Foxo1 axis and how ITGA2 is regulated in the ovarian cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Collagen-rich omentum is a premetastatic niche for integrin α2-mediated peritoneal metastasis

Huang

Liang

Ritz

et al. 2020

eLife

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The extracellular matrix (ECM) plays critical roles in tumor progression and metastasis. However, the contribution of ECM proteins to early metastatic onset in the peritoneal cavity remains unexplored. Here, we suggest a new route of metastasis through the interaction of integrin alpha 2 (ITGA2) with collagens enriched in the tumor coinciding with poor outcome in patients with ovarian cancer. Using multiple gene-edited cell lines and patient-derived samples, we demonstrate that ITGA2 triggers cancer cell adhesion to collagen, promotes cell migration, anoikis resistance, mesothelial clearance, and peritoneal metastasis in vitro and in vivo. Mechanistically, phosphoproteomics identify an ITGA2-dependent phosphorylation of focal adhesion kinase and mitogen-activated protein kinase pathway leading to enhanced oncogenic properties. Consequently, specific inhibition of ITGA2-mediated cancer cell-collagen interaction or targeting focal adhesion signaling may present an opportunity for therapeutic intervention of metastatic spread in ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

Collagen-rich omentum is a premetastatic niche for integrin α2-mediated peritoneal metastasis

Huang

Liang

Ritz

et al. 2020

eLife

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“…Integrins activate several signal transduction pathways, and aberrant expressions of integrins have been detected in several types of cancers; overexpression of integrins can enhance cancer cell development and progression [48][49][50][51]. ITGA2 forms a homodimer with ITGB1, and dysregulated levels of ITGA2/ITGB1 can mediate the signal pathways that enhance malignant transformation in multiple types of cancer cells [52][53][54][55]. In hepatocellular carcinoma cells, ITGA2 inhibits MST1 kinase phosphorylation and activates YAP pro-oncogenic activities [52].…”

Section: Discussionmentioning

confidence: 99%

“…In ovarian cancer cells, expressions of ITGA2 enhance AKT phosphorylation and further accelerate the phosphorylation of the oncogenic protein FOXO1. Moreover, a knockdown assay of ITGA2 has shown that sensitivity of paclitaxel is improved in paclitaxel-resistant ovarian cancer cells [54]. Furthermore, ITGA2 controls the MAPK pathways and EMT in gastric cancer cells, and these events closely contribute to the chemo-resistance of gastric cancer [55].…”

Section: Discussionmentioning

confidence: 99%

Role of miR-30a-3p Regulation of Oncogenic Targets in Pancreatic Ductal Adenocarcinoma Pathogenesis

Shimomura

Okada

Tanaka

et al. 2020

IJMS

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Our recent studies have implicated some passenger strands of miRNAs in the molecular pathogenesis of human cancers. Analysis of the microRNA (miRNA) expression signature in pancreatic ductal adenocarcinoma (PDAC) has shown that levels of miR-30a-3p, the passenger strand derived from pre-mir-30a, are significantly downregulated in PDAC tissues. This study aimed to identify the oncogenes closely involved in PDAC molecular pathogenesis under the regulation of miR-30a-3p. Ectopic expression assays showed that miR-30a-3p expression inhibited the aggressiveness of the PDAC cells, suggesting that miR-30a-3p acts as a tumor-suppressive miRNA in PDAC cells. We further identified 102 putative targets of miR-30a-3p regulation in PDAC cells by combining in silico analysis with gene expression data. Of these, ten genes (EPS8, HMGA2, ENDOD1, SLC39A10, TGM2, MGLL, SERPINE1, ITGA2, DTL, and UACA) were independent prognostic factors in multivariate analysis of survival of patients with PDAC (p < 0.01). We also investigated the oncogenic function of the integrin ITGA2 in PDAC cell lines. The integrin family comprises cell adhesion molecules expressed as heterodimeric, transmembrane proteins on the surface of various cells. Overexpression of ITGA2/ITGB1 (an ITGA2 binding partner) was detected in the PDAC clinical specimens. The knockdown of ITGA2 expression attenuated the malignant phenotypes of the PDAC cells. Together, results from these microRNA-based approaches can accelerate our understanding of PDAC molecular pathogenesis.

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“…In this progress, non-coding RNAs is the most common molecular pathway that dually mediate or inhibit PTX resistance ( Datta et al, 2019 ; Yang et al, 2020 ). Integrin subunit α2 (ITGA2) is an oncogene factor which promotes metastasis and growth ability of cancer cells and it is thought to reduce sensitivity of cancer cells of PTX through activation of Akt/FoxO1 signaling pathway ( Ma et al, 2020 ; Qin et al, 2020 ). Furthermore, high mobility group box 1 (HMGB1) can activate c-Myc oncogene to induce PTX resistance ( Jung et al, 2020 ; Lei et al, 2020 ).…”

Section: Resistance In Taxanesmentioning

confidence: 99%

Mechanisms of Pharmaceutical Therapy and Drug Resistance in Esophageal Cancer

Mao

Zeng

Zhang

et al. 2021

Front. Cell Dev. Biol.

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Pharmaceutical therapies are essential for esophageal cancer (EC). For the advanced EC, the neoadjuvant therapy regimen, including chemotherapy plus radiotherapy and/or immunotherapy, is effective to achieve clinical benefit, even pathological complete response. For the unresectable, recurrent, and metastatic EC, the pharmaceutical therapy is the limited effective regimen to alleviate the disease and prolong the progression-free survival and overall survival. In this review, we focus on the pharmaceutical applications in EC treatment including cytotoxic agents, molecular targeted antibodies, and immune checkpoint inhibitors (ICIs). The chemotherapy regimen is based on cytotoxic agents such as platinum-based complexes, fluorinated pyrimidines and taxenes. Although the cytotoxic agents have been developed in past decades, the standard chemotherapy regimen is still the cisplatin and 5-FU or paclitaxel because the derived drugs have no significant advantages of overcoming the shortcomings of side effects and drug resistance. The targeted molecular therapy is an essential supplement for chemotherapy; however, there are only a few targeted therapies available in clinical practice. Trastuzumab and ramucirumab are the only two molecular therapy drugs which are approved by the US Food and Drug Administration to treat advanced and/or metastatic EC. Although the targeted therapy usually achieves effective benefits in the early stage therapy of EC, the patients will always develop drug resistance during treatment. ICIs have had a significant impact on routine clinical practice in cancer treatment. The anti-programmed cell death-1 monoclonal antibodies pembrolizumab and nivolumab, as the ICIs, are recommended for advanced EC by several clinical trials. However, the significant issues of pharmaceutical treatment are still the dose-limiting side effects and primary or secondary drug resistance. These defects of pharmaceutical therapy restrain the clinical application and diminish the effectiveness of treatment.

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Overexpressed ITGA2 contributes to paclitaxel resistance by ovarian cancer cells through the activation of the AKT/FoxO1 pathway

Cited by 39 publications

References 42 publications

Collagen-rich omentum is a premetastatic niche for integrin α2-mediated peritoneal metastasis

Collagen-rich omentum is a premetastatic niche for integrin α2-mediated peritoneal metastasis

Role of miR-30a-3p Regulation of Oncogenic Targets in Pancreatic Ductal Adenocarcinoma Pathogenesis

Mechanisms of Pharmaceutical Therapy and Drug Resistance in Esophageal Cancer

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