JAK/STAT3 signaling is required for TGF-β-induced epithelial-mesenchymal transition in lung cancer cells

Liu, Rengyun; Zeng, Yuanyuan; Li, Zhe; Wang, Longqiang; Yang, Haiping; Liu, Zeyi; Zhao, Jun; Zhang, Hong Tao

doi:10.3892/ijo.2014.2310

Cited by 255 publications

(191 citation statements)

References 48 publications

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“…In addition, increasing evidence supports that Stat3 has an important role in EMT of cancer cells. [24][25][26] As shown in Supplementary Figure S3 Table S5). …”

Section: Discussionmentioning

confidence: 91%

MicroRNA-19 triggers epithelial–mesenchymal transition of lung cancer cells accompanied by growth inhibition

Yang

Yan

et al. 2015

Laboratory Investigation

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The miR-19 family (miR-19a and miR-19b-1) are key oncogenic components of the miR-17-92 cluster. Overexpression of miR-19 is strongly associated with cancer invasion and metastasis, and poor prognosis of cancer patients. However, the underlying mechanisms remain largely unknown. In the present study, we found that enforced expression of miR-19 including miR-19a and miR-19b-1 triggered epithelial-mesenchymal transition (EMT) of lung cancer cells A549 and HCC827 as shown by mesenchymal-like morphological conversion, downregulation of epithelial proteins (e.g., E-cadherin, ZO-1 (zona occludens 1), and α-catenin), upregulation of mesenchymal proteins (e.g., vimentin, fibronectin 1, N-cadherin, and snail1), formation of stress fibers, and reduced cell adhesion. In addition, enhanced migration and invasion were observed in the cancer cells A549 and HCC827 undergoing EMT. In contrast, silencing of endogenous miR-19 reversed EMT and reduced the migration and invasion abilities of A549 and HCC827 cells. DNA microarray results revealed significant changes of the expression of genes related to EMT, migration, and metastasis of miR-19-expressing A549 cells. Moreover, siRNA-mediated knockdown of PTEN, a target of miR-19, also resulted in EMT, migration, and invasion of A549 and HCC827 cells, suggesting that PTEN is involved in miR-19-induced EMT, migration and invasion of lung cancer cells. Furthermore, lung cancer cells undergoing EMT induced by miR-19 demonstrated reduced proliferation in vitro and in vivo, and enhanced resistance to apoptosis caused by TNF-α. Taken together, these findings suggest that miR-19 triggers EMT, which has an important role in the invasion and migration of lung cancer cells, accompanied by the reduced proliferation of cells.

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“…In addition, increasing evidence supports that Stat3 has an important role in EMT of cancer cells. [24][25][26] As shown in Supplementary Figure S3 Table S5). …”

Section: Discussionmentioning

confidence: 91%

MicroRNA-19 triggers epithelial–mesenchymal transition of lung cancer cells accompanied by growth inhibition

Yang

Yan

et al. 2015

Laboratory Investigation

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“…Similarly, JAK/STAT3 activity is required for TGF-b-mediated Snail induction, EMT, and increased cell migration and invasion. 99 In fact, TGF-b itself has been reported to induce the phosphorylation of JAK1, STAT1, STAT3, and STAT5, 100 although this may be indirect, as TGF-b signaling induces IL-6 production, which can act in autocrine fashion to activate canonical JAK/STAT3 signaling. [101][102][103][104][105][106] Together, these studies support the cooperative intersection of activated-STAT3-and TGF-b-mediated signaling effectors.…”

Section: Discussionmentioning

confidence: 99%

STAT3-mediated SMAD3 activation underlies Oncostatin M-induced Senescence

et al. 2017

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Cytokines in the developing tumor microenvironment (TME) can drive transformation and subsequent progression toward metastasis. Elevated levels of the Interleukin-6 (IL-6) family cytokine Oncostatin M (OSM) in the breast TME correlate with aggressive, metastatic cancers, increased tumor recurrence, and poor patient prognosis. Paradoxically, OSM engages a tumor-suppressive, Signal Transducer and Activator of Transcription 3 (STAT3)-dependent senescence response in normal and non-transformed human mammary epithelial cells (HMEC). Here, we identify a novel link between OSM-activated STAT3 signaling and the Transforming Growth Factor-b (TGF-b) signaling pathway that engages senescence in HMEC. Inhibition of functional TGF-b/SMAD signaling by expressing a dominant-negative TGF-b receptor, treating with a TGF-b receptor inhibitor, or suppressing SMAD3 expression using a SMAD3-shRNA prevented OSMinduced senescence. OSM promoted a protein complex involving activated-STAT3 and SMAD3, induced the nuclear localization of SMAD3, and enhanced SMAD3-mediated transcription responsible for senescence. In contrast, expression of MYC (c-MYC) from a constitutive promoter abrogated senescence and strikingly, cooperated with OSM to promote a transformed phenotype, epithelial-mesenchymal transition (EMT), and invasiveness. Our findings suggest that a novel STAT3/SMAD3-signaling axis is required for OSM-mediated senescence that is coopted during the transformation process to confer aggressive cancer cell properties. Understanding how developing cancer cells bypass OSM/STAT3/SMAD3-mediated senescence may help identify novel targets for future "pro-senescence" therapies aiming to reengage this hidden tumor-suppressive response.

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“…Collectively, galunisertib treatment effectively inhibits the intrinsically elevated ALK5/ Smad3 pathway, leading to a diminution in collagen production by abnormal MSCs. Interestingly, we also observed decreased p-STAT3 by TGF-β blockade, which may result from the modulation of interacting pathways (62,63) important for regulation of collagen production and inflammation related to IL-6 (64).…”

Section: W515lmentioning

confidence: 99%