Tensin3 Is a Negative Regulator of Cell Migration and All Four Tensin Family Members Are Downregulated in Human Kidney Cancer

Martuszewska, Danuta; Ljungberg, Börje; Johansson, Martin; Landberg, Göran; Oslakovic, Cecilia; Dahlbäck, Björn; Hafizi, Sassan

doi:10.1371/journal.pone.0004350

Cited by 61 publications

(86 citation statements)

References 31 publications

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“…DLC1 is a tumor suppressor, but the role of tensin3 or cten in tumorigenesis is less well defined (18)(19)(20)(21)(22)(23). To address whether the tensin3/cten-DLC1 complexes play a role in tumorigenesis, we examined ability of colony formation in soft agar by HEK293 cells that were made to express full-length or a truncated versions of DLC1, tensin3, or cten, individually or in various combination.…”

Section: Resultsmentioning

confidence: 99%

“…Although deregulation of tensin expression is frequently associated with cancer (18)(19)(20), the roles of the different tensins in tumorigenesis and metastasis remain largely undefined and, in some cases, controversial. Whereas all four family members are down-regulated in human kidney cancers (21), elevated cten expression was correlated with thymoma and lung cancer progression (18,20). In invasive breast cancer, cten expression correlates with high epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 levels and metastasis to lymph nodes (22).…”

mentioning

confidence: 99%

“…In invasive breast cancer, cten expression correlates with high epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 levels and metastasis to lymph nodes (22). Both tensin1 and tensin3 have been shown to regulate cell migration and invasive behavior (21,23).…”

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confidence: 99%

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Differential regulation of the activity of deleted in liver cancer 1 (DLC1) by tensins controls cell migration and transformation

Cao

Voss

Zhao

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

102

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The epithelial growth factor receptor plays an important role in cell migration and cancer metastasis, but the underlying molecular mechanism is not fully understood. We show here that differential regulation of the rhodopsin-GTPase-activating (Rho-GAP) activity of deleted in liver cancer 1 (DLC1) by tensin3 and COOH-terminal tensin-like protein (cten) controls EGF-driven cell migration and transformation. Tensin3 binds DLC1 through its actin-binding domain, a region that is missing in cten, and thereby releases an autoinhibitory interaction between the sterile alpha motif and Rho-GAP domains of DLC1. Consequently, tensin3, but not cten, promotes the activation of DLC1, which, in turn, leads to inactivation of RhoA and decreased cell migration. Depletion of endogenous tensin3, but not cten, augmented the formation of actin stress fibers and focal adhesions and enhanced cell motility. These effects were, however, ablated by an inhibitor of the Rho-associated protein kinase. Importantly, activation of DLC1 by tensin3 or its actin-binding domain drastically reduced the anchorage-independent growth of transformed cells. Our study therefore links dynamic regulation of tensin family members by EGF to Rho-GAP through DLC1 and suggests that the tensin-DLC1-RhoA signaling axis plays an important role in tumorigenesis and cancer metastasis, and may be explored for cancer intervention.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Differential regulation of the activity of deleted in liver cancer 1 (DLC1) by tensins controls cell migration and transformation

Cao

Voss

Zhao

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

102

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“…This could be attributed to the origin of the cell line used. Like afadin, the expression of several actin-binding proteins (a-actinin, gelsolin, tensin-3 and profilin-1) weakens the phenotype of transformed cells (Tanaka et al, 1995;Nikolopoulos et al, 2000;Zou et al, 2007;Martuszewska et al, 2009). However, effects can be opposite in non-epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

Loss of AF6/afadin, a marker of poor outcome in breast cancer, induces cell migration, invasiveness and tumor growth

et al. 2011

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Afadin/AF6, an F-actin-binding protein, is ubiquitously expressed in epithelia and has a key role during development, through its regulatory role in cell-cell junction organization. Afadin loss of expression in 15% of breast carcinoma is associated with adverse prognosis and increased risk of metastatic relapse. To determine the role of afadin in breast cancer, we studied the functional consequences of afadin protein extinction using in vitro and in vivo models. Three different breast cancer cell lines representative of the major molecular subtypes were stably repressed for afadin expression (knockdown of afadin (afadin KD)) using RNA interference. Collective and individual migrations as well as Matrigel invasion were markedly increased in afadin KD cells. Heregulin-b1 (HRG-b1)-induced migration and invasion were increased by twofold in afadin KD cells. Conversely, ectopic expression of afadin in the afadin-negative T47D cell line inhibited spontaneous and HRG-b1-induced migrations. RAS/MAPK and SRC kinase pathways were activated in afadin KD cells. Activation levels positively correlated with migration and invasion strength. Use of MEK1/2 (U0126) and SRC kinases (SU6656) inhibitors reduced afadin-dependent migration and invasion. Afadin extinction in the SK-BR-3 cell line markedly accelerated tumor growth development in mouse mammary gland and lung metastasis formation. These results may explain why the loss of afadin expression in tumors correlates with high tumor size and poor metastasis-free survival in patients.

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“…36 However, complete genomic DNA gains at the probes spanning HGF were only observed in three cases ( Figure 1). On the other hand, DNA losses tended to be small focal changes and recurrently mapped to 7p22, 7p12.3, and 7q11.23 in which three earlier reported candidate tumor suppressor genes, that is MAD1L1 (7p22.3), 37 TNS3 (7p12.3), 38 and CLDN4 (7q11.23), 39 were located. …”

Section: Genomic Profiling Of Chromosome 7 By Ultrahigh-resolution Acghmentioning

confidence: 93%

Prognostic implication of MET overexpression in myxofibrosarcomas: an integrative array comparative genomic hybridization, real-time quantitative PCR, immunoblotting, and immunohistochemical analysis

Lee

Fang

et al. 2010

Modern Pathology

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It remains obscure in myxofibrosarcoma about the basis of tumorigenesis, progression, and metastasis. Chromosome 7 gains are common in some sarcomas, including myxofibrosarcoma, whereas the specific oncogenes are yet to be characterized. We performed an integrative study of MET gene at 7q31.2 to elucidate its implication in myxofibrosarcoma. Focused on candidate oncogenes on chromosome 7, 385K array comparative genomic hybridization was used to profile DNA copy number alterations of 12 samples. MET transcript was successfully quantified by real-time RT-PCR for 16 laser-microdissected tumors and two myxofibrosarcoma cell lines (NMFH-1, OH931). MET immunoexpression was assessable in 86 primary localized tumors with followup. To analyze endogenous MET expression and activation, NMFH-1 and OH931 cells, both with wild-type MET gene, were subjected to Western blotting and hepatocyte growth factor-treated NMFH-1 cells were evaluated for the kinetics of MET tyrosine phosphorylation. Non-random large-scale gains on 7q were detected in five cases, delineating three recurrent amplicons, 7q21.11-7q21.3, 7q22.1-22.3, and 7q31.1-7q32.3, in which the locus of MET displayed increased copy number, among others. MET mRNA was upregulated in OH931, NMFH-1, and nine tumors (56%), whereas neither gene dosage nor mRNA expression of MET was associated with clinicopathological factors. In contrast, MET protein overexpression, present in 67% of cases, was highly related to deep location (P ¼ 0.004), higher grades (P ¼ 0.001), and more advanced stages (Po0.001). Importantly, MET overexpression independently portended inferior metastasis-free survival (P ¼ 0.004) and overall survival (P ¼ 0.0221). Expressing activating phospho-MET at Tyr 1234 /Tyr 1235 , OH931 cells had more abundant total MET than NMFH-1 cells, whereas the latter became promptly phosphorylated on stimulation of

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Tensin3 Is a Negative Regulator of Cell Migration and All Four Tensin Family Members Are Downregulated in Human Kidney Cancer

Cited by 61 publications

References 31 publications

Differential regulation of the activity of deleted in liver cancer 1 (DLC1) by tensins controls cell migration and transformation

Differential regulation of the activity of deleted in liver cancer 1 (DLC1) by tensins controls cell migration and transformation

Loss of AF6/afadin, a marker of poor outcome in breast cancer, induces cell migration, invasiveness and tumor growth

Prognostic implication of MET overexpression in myxofibrosarcomas: an integrative array comparative genomic hybridization, real-time quantitative PCR, immunoblotting, and immunohistochemical analysis

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