Cell polarity and cancer – cell and tissue polarity as a non-canonical tumor suppressor

Lee, Minhui; Vasioukhin, Valeri

doi:10.1242/jcs.016634

Cited by 255 publications

(237 citation statements)

References 114 publications

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“…Although our present understanding of the protein complexes involved in the generation of polarity has been dealt with in more specialized reviews (Dow and Humbert, 2007;Lee and Vasioukhin, 2008), to understand the significance of the alteration in the expression of cell polarity genes during tumour development, we will briefly summarize the epithelial cell polarity systems. Epithelial cells maintain two types of cell polarity, planar and apical-basal polarity (Dow and Humbert, 2007).…”

Section: Polarity-generating Protein Complexes At a Glancementioning

confidence: 99%

“…Lgl proteins of the Scrib complex compete with Par3 for binding to the Par complex, thereby sequestering the active Par complex away from the apical junction domain (Figure 1). Conversely, Lgl phosphorylation by aPKC inactivates the SCRIB complex (reviewed by Assemat et al, 2008;Lee and Vasioukhin, 2008). …”

Section: Polarity-generating Protein Complexes At a Glancementioning

confidence: 99%

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Transcriptional regulation of cell polarity in EMT and cancer

2008

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The epithelial-to-mesenchymal transition (EMT) is a crucial process in tumour progression providing tumour cells with the ability to escape from the primary tumour, to migrate to distant regions and to invade tissues. EMT requires a loss of cell-cell adhesion and apical-basal polarity, as well as the acquisition of a fibroblastoid motile phenotype. Several transcription factors have emerged in recent years that induce EMT, with important implications for tumour progression. However, their effects on cell polarity remain unclear. Here, we have re-examined the data available related to the effect of EMT related transcription factors on epithelial cell plasticity, focusing on their impact on cell polarity. Transcriptional and post-transcriptional regulatory mechanisms mediated by several inducers of EMT, in particular the ZEB and Snail factors, downregulate the expression and/or functional organization of core polarity complexes. We also summarize data on the expression of cell polarity genes in human tumours and analyse genetic interactions that highlight the existence of complex regulatory networks converging on the regulation of cell polarity by EMT inducers in human breast carcinomas. These recent observations provide new insights into the relationship between alterations in cell polarity components and EMT in cancer, opening new avenues for their potential use as therapeutic targets to prevent tumour progression.

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Section: Polarity-generating Protein Complexes At a Glancementioning

confidence: 99%

Section: Polarity-generating Protein Complexes At a Glancementioning

confidence: 99%

Transcriptional regulation of cell polarity in EMT and cancer

2008

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“…Meanwhile, disruption of cell polarity and tissue disorganization is a hallmark of advanced epithelial tumours 2 . AF6 (also known as afadin and MLLT4) is well known as a key molecule essential for structural organization of cell-cell junctions and development.…”

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confidence: 99%

Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression

Chang

Peng

et al. 2015

Nat Commun

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Pancreatic cancer (PC) is a particularly lethal form of cancer with high potential for metastasis to distant organs. Disruption of cell polarity is a hallmark of advanced epithelial tumours. Here we show that the polarity protein AF6 (afadin and MLLT4) is expressed at low levels in PC. We demonstrate that depletion of AF6 markedly promotes proliferation and metastasis of PC cells through upregulation of the expression of Snail protein, and this requires the nuclear localization of AF6. Furthermore, AF6 deficiency in PC cells leads to increased formation of a Dishevelled 2 (Dvl2)-FOXE1 complex on the promoter region of Snail gene, and activation of Snail expression. Altogether, our data established AF6 as a potential inhibitor of metastasis in PC cells. Targeting the Dvl2-FOXE1-Snail signalling axis may thus represent a promising therapeutic strategy.

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“…ccRCCs are characterized by loss of cell-cell junctions and of basoapical polarity and increased cell proliferation. 10 Recent data suggest that inactivation of the VHL tumor suppressor gene in RCC causes the disruption of adherens and tight junctions through hypoxia-inducible factor (HIF)-independent mechanisms. 11 Epithelial cell polarity is also regulated by membrane-associated polarity complexes, such as the Scribble, Partition Defective Protein (PAR) and Crumbs complexes, that are conserved in metazoans.…”

mentioning

confidence: 99%

“…16 In humans, cell transformation is associated with loss of cell polarity and changes in the expression of polarity genes and in the subcellular localization of the corresponding proteins. 10 For instance, homozygous deletion of PARD3 (the gene that encodes the PAR-3 protein) has been detected in primary esophageal squamous cell carcinomas in which decreased PARD3 mRNA levels are observed in more than two thirds of cases. 17 However, PAR-3 deregulation in ccRCC has never been investigated and its prognostic value is unknown.…”

mentioning

confidence: 99%

Overexpression of the polarity protein PAR‐3 in clear cell renal cell carcinoma is associated with poor prognosis

Dugay

Goff²,

Rioux-Leclerq

et al. 2013

Intl Journal of Cancer

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The partition-defective 3 (PAR-3) protein is implicated in the development and maintenance of cell polarity and is associated with proteins that mediate the changes in cytoskeleton organization required for cell polarity establishment. In this work, we used two original primary cell lines (R-180 and R-305) derived from clear cell Renal Cell Carcinoma (ccRCC) surgical specimens of a patient with unfavorable clinical course (R-180 cells) and a patient with favorable prognosis (R-305 cells) to identify genetic and molecular features that may explain the survival difference of the two patients. The cytogenetic analysis of these cell lines revealed that the PARD3 gene was amplified only in the R-180 cell line that was derived from an aggressive ccRCC. PARD3 gene amplification was associated with overexpression of the encoded protein and altered cytoskeleton organization. Consistently, PARD3 knockdown in R-180 cells restored the cytoskeleton organization and reduced cell migration in comparison to non-transfected cells. Immunohistochemical analysis of ccRCC samples from a cohort of 96 patients with a follow-up of 6 years revealed that PAR-3 overexpression was correlated with poor survival. Our results suggest that PAR-3 has a role in the clinical aggressiveness of ccRCC, possibly by promoting cell migration.Renal cell carcinoma (RCC), the incidence of which is steadily increasing, represents approximately 3.8% of adult malignancies and 90-95% of kidney neoplasms. 1 The most common histological RCC subtype is the conventional or clear cell carcinoma (ccRCC), which accounts for 70-75% of cases. 2,3 At least 60% of ccRCCs have deletions or translocations involving the short arm of chromosome 3, which contains the von Hippel-Lindau (VHL) gene at 3p25. 4,5

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Cell polarity and cancer – cell and tissue polarity as a non-canonical tumor suppressor

Cited by 255 publications

References 114 publications

Transcriptional regulation of cell polarity in EMT and cancer

Transcriptional regulation of cell polarity in EMT and cancer

Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression

Overexpression of the polarity protein PAR‐3 in clear cell renal cell carcinoma is associated with poor prognosis

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