Paxillin family of focal adhesion adaptor proteins and regulation of cancer cell invasion

Alpha, Kyle M; Xu, Weiyi; Turner, Christopher E.

doi:10.1016/bs.ircmb.2020.05.003

Cited by 35 publications

(30 citation statements)

References 270 publications

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“…For subsequent analyses, we focused on miR-139-3p (the passenger strand) target genes, according to our previous studies emphasizing the novel roles of miRNA passenger strands. Among these target genes, we focused on PXN , which showed the most significant association with RCC patient survival in the multivariate analysis and has been reported previously as an oncogene in other types of cancers [ 18 , 19 ].…”

Section: Resultsmentioning

confidence: 99%

Regulation of Oncogenic Targets by the Tumor-Suppressive miR-139 Duplex (miR-139-5p and miR-139-3p) in Renal Cell Carcinoma

et al. 2020

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We previously found that both the guide and passenger strands of the miR-139 duplex (miR-139-5p and miR-139-3p, respectively) were downregulated in cancer tissues. Analysis of TCGA datasets revealed that low expression of miR-139-5p (p < 0.0001) and miR-139-3p (p < 0.0001) was closely associated with 5-year survival rates of patients with renal cell carcinoma (RCC). Ectopic expression assays showed that miR-139-5p and miR-139-3p acted as tumor-suppressive miRNAs in RCC cells. Here, 19 and 22 genes were identified as putative targets of miR-139-5p and miR-139-3p in RCC cells, respectively. Among these genes, high expression of PLXDC1, TET3, PXN, ARHGEF19, ELK1, DCBLD1, IKBKB, and CSF1 significantly predicted shorter survival in RCC patients according to TCGA analyses (p < 0.05). Importantly, the expression levels of four of these genes, PXN, ARHGEF19, ELK1, and IKBKB, were independent prognostic factors for patient survival (p < 0.05). We focused on PXN (paxillin) and investigated its potential oncogenic role in RCC cells. PXN knockdown significantly inhibited cancer cell migration and invasion, possibly by regulating epithelial–mesenchymal transition. Involvement of the miR-139-3p passenger strand in RCC molecular pathogenesis is a new concept. Analyses of tumor-suppressive-miRNA-mediated molecular networks provide important insights into the molecular pathogenesis of RCC.

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Section: Resultsmentioning

confidence: 99%

Regulation of Oncogenic Targets by the Tumor-Suppressive miR-139 Duplex (miR-139-5p and miR-139-3p) in Renal Cell Carcinoma

et al. 2020

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“…Therefore, PSCs activation is considered to be the core event in the development of pancreatic fibrosis, suggesting that targeting PSCs is a potential strategy for CP therapy. Hydrogen peroxide-inducible clone-5 (Hic-5) is a member of the paxillin family, which acts as a molecular scaffold, and its expression leads to a poor prognosis in PC patients [ 47 ]. In caerulein-induced CP, the expression of Hic-5 was strongly up-regulated in activated PSCs in the fibrotic tissue [ 48 ].…”

Section: The Role Of Fibrosis In Pancreatitismentioning

confidence: 99%

Targeting Fibrosis: The Bridge That Connects Pancreatitis and Pancreatic Cancer

Huang

Iovanna

Santofimia‐Castaño

2021

IJMS

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Pancreatic fibrosis is caused by the excessive deposits of extracellular matrix (ECM) and collagen fibers during repeated necrosis to repair damaged pancreatic tissue. Pancreatic fibrosis is frequently present in chronic pancreatitis (CP) and pancreatic cancer (PC). Clinically, pancreatic fibrosis is a pathological feature of pancreatitis and pancreatic cancer. However, many new studies have found that pancreatic fibrosis is involved in the transformation from pancreatitis to pancreatic cancer. Thus, the role of fibrosis in the crosstalk between pancreatitis and pancreatic cancer is critical and still elusive; therefore, it deserves more attention. Here, we review the development of pancreatic fibrosis in inflammation and cancer, and we discuss the therapeutic strategies for alleviating pancreatic fibrosis. We further propose that cellular stress response might be a key driver that links fibrosis to cancer initiation and progression. Therefore, targeting stress proteins, such as nuclear protein 1 (NUPR1), could be an interesting strategy for pancreatic fibrosis and PC treatment.

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“…Paxillin (Turner et al, 1990) is a scaffold/adapter protein that localizes to sites of cell-ECM interaction, called focal adhesions, and plays various critical roles in the ECM-integrin signaling network (Turner, 2000;Brown and Turner, 2004;Deakin and Turner, 2008;Scheswohl et al, 2008;López-Colomé et al, 2017;Alpha et al, 2020). In cancer cells activated by ECM signals, paxillin also recruits GTPase activating proteins (GAPs) and guanine-nucleotide exchange factors (GEFs) and Rho GTPase effector proteins to focal adhesion sites to coordinate the spatio-temporal activity of Rho GTPases and downstream signaling (Turner et al, 1999;Schaller, 2001;Brown et al, 2002;LaLonde et al, 2006;Deakin et al, 2012;López-Colomé et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Paxillin promotes breast tumor collective cell invasion through maintenance of adherens junction integrity

Alpha

Zehrbach

et al. 2022

MBoC

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Distant organ metastasis is linked to poor prognosis during cancer progression. The expression level of the focal adhesion adapter protein paxillin varies among different human cancers, but its role in tumor progression is unclear. Herein, we utilize a newly generated PyMT mammary tumor mouse model with conditional paxillin ablation in breast tumor epithelial cells, combined with in vitro 3D tumor organoids invasion analysis and 2D calcium switch assays, to assess the roles for paxillin in breast tumor cell invasion. Paxillin had little effect on primary tumor initiation and growth but is critical for the formation of distant lung metastasis. In paxillin-depleted 3D tumor organoids, collective cell invasion was substantially perturbed. Two-dimensional cell culture revealed paxillin-dependent stabilization of adherens junctions (AJ). Mechanistically, paxillin is required for AJ assembly through facilitating E-cadherin endocytosis and recycling and HDAC6-mediated microtubule acetylation. Furthermore, Rho GTPase activity analysis and rescue experiments with a RhoA activator or Rac1 inhibitor suggest paxillin is potentially regulating the E-cadherin-dependent junction integrity and contractility through control of the balance of RhoA and Rac1 activities. Together, these data highlight new roles for paxillin in the regulation of cell-cell adhesion and collective tumor cell migration to promote the formation of distance organ metastases. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text]

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Paxillin family of focal adhesion adaptor proteins and regulation of cancer cell invasion

Cited by 35 publications

References 270 publications

Regulation of Oncogenic Targets by the Tumor-Suppressive miR-139 Duplex (miR-139-5p and miR-139-3p) in Renal Cell Carcinoma

Regulation of Oncogenic Targets by the Tumor-Suppressive miR-139 Duplex (miR-139-5p and miR-139-3p) in Renal Cell Carcinoma

Targeting Fibrosis: The Bridge That Connects Pancreatitis and Pancreatic Cancer

Paxillin promotes breast tumor collective cell invasion through maintenance of adherens junction integrity

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