Stat3 Activity Is Required for Gap Junctional Permeability in Normal Rat Liver Epithelial Cells

Geletu, Mulu; Chaize, Chrystele; Arulanandam, Rozanne; Vultur, Adina; Kowolik, Claudia; Anagnostopoulou, Aikaterini; Jove, Richard; Raptis, Leda

doi:10.1089/dna.2008.0833

Cited by 12 publications

(23 citation statements)

References 43 publications

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“…A high degree of Stat3 knockdown by shRNA causes apoptosis, as has been reported previously by others (23,35). In the generation of stable shRNA-expressing cell lines in this study, only viable cells that had moderate knockdown survived the selection process and were selected for analyses.…”

Section: Resultssupporting

confidence: 59%

Doubles Game: Src-Stat3 versus p53-PTEN in Cellular Migration and Invasion

Mukhopadhyay¹,

Mooney²,

Jia³

et al. 2010

Molecular and Cellular Biology

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We have recently shown that Src induces the formation of podosomes and cell invasion by suppressing endogenous p53, while enhanced p53 strongly represses the Src-induced invasive phenotype. However, the mechanism by which Src and p53 play antagonistic roles in cell invasion is unknown. Here we show that the Stat3 oncogene is a required downstream effector of Src in inducing podosome structures and related invasive phenotypes. Stat3 promotes Src phenotypes through the suppression of p53 and the p53-inducible protein caldesmon, a known podosome antagonist. In contrast, enhanced p53 attenuates Stat3 function and Srcinduced podosome formation by upregulating the tumor suppressor PTEN. PTEN, through the inactivation of Src/Stat3 function, also stabilizes the podosome-antagonizing p53/caldesmon axis, thereby further enhancing the anti-invasive potential of the cell. Furthermore, the protein phosphatase activity of PTEN plays a major role in the negative regulation of the Src/Stat3 pathway and represses podosome formation. Our data suggest that cellular invasiveness is dependent on the balance between two opposing forces: the proinvasive oncogenes Src-Stat3 and the anti-invasive tumor suppressors p53-PTEN.p53 is a potent tumor suppressor that plays a critical role in the regulation of cell cycle progression, DNA repair, apoptosis, and senescence (3,10,32,57). Approximately half of all human tumors have compromised p53 function (25, 62). Loss of p53 function has also been implicated in the evolution of aggressive and metastatic cancers (28,33,42,43), suggesting an antiinvasive and migration role of p53. Recent studies have increasingly unveiled this relatively less known aspect of p53 function in the regulation of cell migration and invasion (19,20,45,63,66). We have recently shown that p53, acting downstream of Src, strongly suppresses the formation of podosomes (also called invadopodia in cancer cells) and extracellular matrix (ECM) digestion by upregulating the expression of caldesmon, a known antagonist of podosomes (44).Src, a proto-oncogenic nonreceptor tyrosine kinase, induces migratory and invasive phenotypes in various cell types by initiating extensive cytoskeletal rearrangements (38,51,67). Activated Src induces the formation of podosomes and rosettes of podosomes, which are dynamic, actin-rich membrane protrusions (9,24,40), specialized in the degradation of the ECM by the recruitment and secretion of matrix metalloproteinases (MMPs) (8,38,60,64

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Section: Resultssupporting

confidence: 59%

Doubles Game: Src-Stat3 versus p53-PTEN in Cellular Migration and Invasion

Mukhopadhyay¹,

Mooney²,

Jia³

et al. 2010

Molecular and Cellular Biology

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“…This evidence indicates a pleiotropic significance of STAT3: That it enables permeability of gap junctions and contributes to maintenance of gap junction communication (3,7). It should be emphasized that, besides Cx expression, STAT3 is an extraordinarily versatile mediator and it interacts with a number of molecules, including leptin and its receptor OB-R, IL-11 or oncostatin M that affect the invasive properties of malignant cells via their impact on cellular adhesion, motility and survival in gynecological cancers (10,(23)(24)(25)(26)(27).…”

Section: Stat3-cx43 Stat3-cx26 --------------------------------------mentioning

confidence: 85%

“…As well as a reduction in E-cadherin expression, stimulation of Src also results in inhibition of GJIC (3). Signal transducer and activator of transcription-3 (STAT3) is a downstream molecule of Src that if activated via phosporyltion acts as an oncogene (3).…”

Section: Introductionmentioning

confidence: 99%

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Association of STAT3 with Cx26 and Cx43 in human uterine endometrioid adenocarcinoma

2016

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Abstract. Signal transducer and activator of transcription-3 (STAT3) drives endometrial carcinogenesis, while signaling via gap junctions gets weakened during cancer progression. Connexin 26 (Cx26), Cx43 and STAT3 were immunohistochemically evaluated in 78 endometrioid adenocarcinomas: Nuclear expression of STAT3 positively correlated with cytoplasmic immunoreactivity to Cx43 (P=0.004, r=0.318) and Cx26 (P=0.006, r=0.309). STAT3 correlated with Cx43 (P=0.022, r=0.411) and Cx26 (P=0.008 r=0.466) in G1 tumors. A statistically significant linkage remained in G2 cancers between STAT3 and Cx43 (P=0.061, r=0.262) and Cx26 (P=0.016, r=0.331); however, no correlations were observed in G3 tumors. STAT3 was significantly associated with Cx 43 (p=0.003, r=0.684) and Cx26 (p=0.049, r=0.500) in estrogen receptor (ER) negative adenocarcinomas. STAT3 did not correlate with Cx43 in ER positive adenocarcinomas; however, STAT3 expression remained correlated with Cx26 expression (P=0.035, r=0.268). In progesterone receptor negative tumors STAT3 was significantly associated with Cx43 (P=0.035, r=0.451) and Cx26 (P<0.0001, r=0.707). However, in PgR positive adenocarcinomas STAT3 correlated with Cx43 (P=0.03, r=0.290) but not with Cx26. Thus, it appears that hormone dependent acceleration of cancer growth breaks the association between STAT3 and Cx expression. These associations become weaker as the tumors dedifferentiate from G1 to G3 endometrioid adenocarcinomas. The present study provides evidence that the loss of correlation between STAT3 and selected Cx proteins occurs in tumors with more aggressive behavior.

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“…Electroporation in situ was employed to examine the role of Stat3 upon GJIC, both in immortalised rat liver epithelial T51B [36] or mouse lung epithelial type II E10 [37] cells both of which normally have extensive GJIC, and in lung cancer lines or primary tumor cells expressing different levels of activated Src [33,38]. …”

Section: Gjic Examinationmentioning

confidence: 99%

Stat3 and Gap Junctions in Normal and Lung Cancer Cells

Guy

Geletu

Arulanandam

et al. 2014

Cancers

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Gap junctions are channels linking the interiors of neighboring cells. A reduction in gap junctional intercellular communication (GJIC) correlates with high cell proliferation, while oncogene products such as Src suppress GJIC, through the Ras/Raf/Erk and other effector pathways. High Src activity was found to correlate with high levels of the Src effector, Signal Transducer and Activator of Transcription-3 (Stat3) in its tyrosine-705 phosphorylated, i.e., transcriptionally activated form, in the majority of Non-Small Cell Lung Cancer lines examined. However, Stat3 inhibition did not restore GJIC in lines with high Src activity. In the contrary, Stat3 inhibition in normal cells or in lines with low Src activity and high GJIC eliminated gap junctional communication. Therefore, despite the fact that Stat3 is growth promoting and in an activated form acts like an oncogene, it is actually required for junctional permeability.

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Stat3 Activity Is Required for Gap Junctional Permeability in Normal Rat Liver Epithelial Cells

Cited by 12 publications

References 43 publications

Doubles Game: Src-Stat3 versus p53-PTEN in Cellular Migration and Invasion

Doubles Game: Src-Stat3 versus p53-PTEN in Cellular Migration and Invasion

Association of STAT3 with Cx26 and Cx43 in human uterine endometrioid adenocarcinoma

Stat3 and Gap Junctions in Normal and Lung Cancer Cells

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