The role of TGF-β and its crosstalk with RAC1/RAC1b signaling in breast and pancreas carcinoma

Melzer, Catharina; Hass, Ralf; Ohe, Juliane von der; Lehnert, Hendrik; Ungefroren, Hendrik

doi:10.1186/s12964-017-0175-0

Cited by 60 publications

(53 citation statements)

References 106 publications

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“…The cells’ response to exogenous and autocrine TGF-β can be suppressed by expressing a dominant-negative TβRII, use of a TGF-β type I receptor inhibitor, or ectopic expression of MYC (a well-known suppressor of TGF-β signaling) which might prevent RAS-mediated OIS, and together with loss of p16 and p53 function, eventually permits the expansion of HMEC with a malignant phenotype. However, cells can also alter intracellular signaling activity autonomously by activating endogenous promoters and inhibitors such as MYC or, as shown here, members of the Rho/Rac family of small GTPases [ 37 ]. Specifically, we have identified Rac1b as a negative regulator of the TGF-β1-induced cell cycle inhibitor p21 WAF1 , thereby acting in a promitotic manner by counteracting TGF-β1-induced growth arrest.…”

Section: Discussionmentioning

confidence: 99%

TGF-β-Dependent Growth Arrest and Cell Migration in Benign and Malignant Breast Epithelial Cells Are Antagonistically Controlled by Rac1 and Rac1b

Melzer

Ohe

Hass

et al. 2017

IJMS

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Despite improvements in diagnosis and treatment, breast cancer is still the most common cancer type among non-smoking females. TGF-β can inhibit breast cancer development by inducing cell cycle arrest in both, cancer cells and, as part of a senescence program in normal human mammary epithelial cells (HMEC). Moreover, TGF-β also drives cell migration and invasion, in part through the small GTPases Rac1 and Rac1b. Depletion of Rac1b or Rac1 and Rac1b in MDA-MB-231 or MDA-MB-435s breast cancer cells by RNA interference enhanced or suppressed, respectively, TGF-β1-induced migration/invasion. Rac1b depletion in MDA-MB-231 cells also increased TGF-β-induced p21WAF1 expression and ERK1/2 phosphorylation. Senescent HMEC (P15/P16), when compared to their non-senescent counterparts (P11/P12), presented with dramatically increased migratory activity. These effects were paralleled by elevated expression of genes associated with TGF-β signaling and metastasis, downregulated Rac1b, and upregulated Rac1. Our data suggest that acquisition of a motile phenotype in HMEC resulted from enhanced autocrine TGF-β signaling, invasion/metastasis-associated gene expression, and a shift in the ratio of antimigratory Rac1b to promigratory Rac1. We conclude that although enhanced TGF-β signaling is considered antioncogenic in HMEC by suppressing oncogene-induced transformation, this occurs at the expense of a higher migration and invasion potential.

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Section: Discussionmentioning

confidence: 99%

TGF-β-Dependent Growth Arrest and Cell Migration in Benign and Malignant Breast Epithelial Cells Are Antagonistically Controlled by Rac1 and Rac1b

Melzer

Ohe

Hass

et al. 2017

IJMS

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“…The small GTPase Rac1 and its closely related isoform Rac1b have been described as protooncogenes in different types of tumors such as pancreatic carcinoma, colorectal carcinoma or mammary adenocarcinoma (Melzer et al, 2017). To delineate the function of both isoforms in lung adenocarcinoma, we determined the total protein levels in different NSCLC cell lines ( Figure 1A).…”

Section: Expression and Cellular Localization Of Rac1 And Rac1b In Lumentioning

confidence: 99%

Different signaling and functionality of Rac1 and Rac1b in the progression of lung adenocarcinoma

Seiz

Klinke

Scharlibbe

et al. 2019

Biological Chemistry

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Rac1 is a ubiquitously expressed Rho GTPase and an important regulator of the actin cytoskeleton. Its splice variant Rac1b exhibits a 19-amino acid (aa) in-frame insertion and is predominantly active. Both proteins were described in tumorigenesis or metastasis. We investigated the contribution of Rac1 and Rac1b to tumor progression of human non-small-cell lung adenocarcinoma (NSCLA). Rac1 protein was present in 8/8 NSCLA cell lines analyzed, whereas Rac1b was expressed in only 6/8. In wound-healing assays, enhanced green fluorescence protein (EGFP)-Rac1 slightly decreased cell migration, whereas proliferation was increased in both, Rac1- and Rac1b-expressing cells. In the in vivo chorioallantoic invasion model, EGFP-Rac1-expressing cells formed more invasive tumors compared to EGFP-Rac1b. This increased invasiveness correlated with enhanced phosphorylation of p38α, AKT and glycogen synthase kinase 3β (GSK3β), and activation of serum response- and Smad-dependent gene promoters by Rac1. In contrast, Rac1b solely activated the mitogen-activated protein kinase (MAPK) JNK2, together with TCF/LEF1- and nuclear factor kappa B (NFκB)-responsive gene reporters. Rac1b, as Rac1, phosphorylated p38α, AKT and GSK3β. Knockdown of the splicing factor epithelial splicing regulatory protein 1 (ESRP1), which mediates out-splicing of exon 3b from Rac1 pre-messenger RNA, resulted in increased Rac1b messenger RNA (mRNA) and suppression of the epithelial-mesenchymal transition (EMT)-associated transcription factor ZEB1. Our data demonstrate different signaling and functional activities of Rac1 and Rac1b and an important role for Rac1 in lung cancer metastasis.

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“…Transforming growth factor-β (TGF-β) is a multifunctional cytokine that participates in the autocrine and paracrine regulation of a variety of biological functions in cells, including the inhibition of epithelial cell, immune cell and hematopoietic cell proliferation, the promotion of angiogenesis, and the induction of fibroblast differentiation from normal epithelial cells, a process of transformation that is closely related to E-cadherin expression (33,34). Our study applied TGF-β as an EMT-inducing factor.…”

Section: Univariable Analysis Multivariable Analysis ----------------mentioning

confidence: 99%

E‑cadherin is downregulated by microenvironmental changes in pancreatic cancer and induces EMT

et al. 2018

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The aim of the present study was to research the effect of microenvironmental change on epithelial‑mesenchymal transition (EMT) in pancreatic cancer cells and to determine the correlation between E‑cadherin expression and the prognosis of pancreatic cancer patients. We established hypoxic, serum‑deficient and TGF‑β‑induced microenvironment models of pancreatic cancer cells and studied the changes in the mRNA and protein expression of EMT‑related molecules, E‑cadherin and vimentin, using western blot analysis and real‑time PCR. Furthermore, immunohistochemistry was used to investigate E‑cadherin expression in pancreatic cancer tissues, and survival analysis and COX regression analysis were conducted. In pancreatic cancer cells under hypoxic, serum‑starved and TGF‑β‑induced microenvironments, E‑cadherin protein and mRNA levels were significantly decreased (P<0.05), while vimentin protein and mRNA expression levels were significantly increased (P<0.05). The results of immunohistochemistry showed that the protein level of E‑cadherin in pancreatic cancer tissues was positively correlated with overall survival (P<0.01). The results of Cox regression analysis showed that E‑cadherin was an independent prognostic factor in pancreatic cancer. In conclusion, E‑cadherin expression was significantly decreased by microenvironment changes, and this decrease induced EMT in pancreatic cancer cells. E‑cadherin is an independent prognostic marker in pancreatic cancer patients.

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The role of TGF-β and its crosstalk with RAC1/RAC1b signaling in breast and pancreas carcinoma

Cited by 60 publications

References 106 publications

TGF-β-Dependent Growth Arrest and Cell Migration in Benign and Malignant Breast Epithelial Cells Are Antagonistically Controlled by Rac1 and Rac1b

TGF-β-Dependent Growth Arrest and Cell Migration in Benign and Malignant Breast Epithelial Cells Are Antagonistically Controlled by Rac1 and Rac1b

Different signaling and functionality of Rac1 and Rac1b in the progression of lung adenocarcinoma

E‑cadherin is downregulated by microenvironmental changes in pancreatic cancer and induces EMT

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