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Loss of Smad4 promotes aggressive lung cancer metastasis by de-repression of PAK3 via miRNA regulation.

ABSTRACT: SMAD4 is mutated in human lung cancer, but the underlying mechanism by which Smad4 loss-of-function (LOF) accelerates lung cancer metastasis is yet to be elucidated. Here, we generate a highly aggressive lung cancer mouse model bearing conditional Kras^G12D, p53^fl/fl LOF and Smad4^fl/fl LOF mutations (SPK), showing a much higher incidence of tumor metastases than the Kras^G12D, p53^fl/fl (PK) mice. Molecularly, PAK3 is identified as a downstream effector of Smad4, mediating metastatic signal transduction via the PAK3-JNK-Jun pathway. Upregulation of PAK3 by Smad4 LOF in SPK mice is achieved by attenuating Smad4-dependent transcription of miR-495 and miR-543. These microRNAs (miRNAs) directly bind to the PAK3 3'UTR for blockade of PAK3 production, ultimately regulating lung cancer metastasis. An inverse correlation between Smad4 and PAK3 pathway components is observed in human lung cancer. Our study highlights the Smad4-PAK3 regulation as a point of potential therapy in metastatic lung cancer.

SUBMITTER: Tan X

PROVIDER: S-EPMC8357888 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Loss of Smad4 promotes aggressive lung cancer metastasis by de-repression of PAK3 via miRNA regulation

Project description:Over 85% of lung cancer patients harbor overt or subclinical metastases at diagnosis, and therefore most patients die of progressive metastatic disease despite aggressive local and systemic therapies. Somatic mutations in the Smad4 gene have been found in non-small-cell lung cancer, but the underlying mechanism by which Smad4 loss-of-function (LOF) accelerates lung cancer metastasis is yet to be elucidated. Here, we generated a highly aggressive lung cancer mouse model bearing conditional KrasG12D, p53fl/fl LOF and/or Smad4 fl/fl LOF mutations. The Smad4fl/fl; p53 fl/fl; KrasG12D (SPK) mutant mice manifested a much higher incidence of tumor metastases than the p53 fl/fl; KrasG12D (PK) mice. Molecularly, PAK3 was identified as a novel downstream effector of Smad4, mediating metastatic signal transduction via the PAK3-JNK-Jun pathway. Upregulation of PAK3 by Smad4 LOF in SPK mice was achieved by attenuating Smad4-dependent transcription of miR-495 and miR-543. These microRNAs (miRNAs) directly bind to the PAK3 3’UTR for blockade of PAK3 production, ultimately regulating lung cancer metastasis. An inverse correlation between Smad4 and PAK3 pathway components suggests clinical use of Smad4 LOF as a potential marker for prognosis in human lung cancer. Our study highlights the Smad4-PAK3 regulation as a point of potential therapy in metastatic lung cancer.

2021-05-07 | GSE164436 | GEO

Loss of Smad4 promotes aggressive lung cancer metastasis by de-repression of PAK3 via miRNA regulation

Project description:Loss of Smad4 promotes aggressive lung cancer metastasis by de-repression of PAK3 via miRNA regulation

| PRJNA690712 | ENA

miRNA-558 promotes gastric cancer progression through attenuating Smad4-mediated repression of heparanase expression.

Project description:Previous studies have indicated that as the only mammalian endo-β-D-glucuronidase, heparanase (HPSE) is up-regulated and associated with poor prognosis in gastric cancer, while the underlying mechanisms still remain to be determined. Herein, through integrative analysis of public datasets, we found microRNA-558 (miR-558) and SMAD family member 4 (Smad4) as the crucial transcription regulators of HPSE expression in gastric cancer, with their adjacent target sites within the promoter of HPSE. We identified that endogenous miR-558 activated the transcription and expression of HPSE in gastric cancer cell lines. In contrast, Smad4 suppressed the nascent transcription and expression of HPSE via directly binding to its promoter. Mechanistically, miR-558 recognized its complementary site within HPSE promoter to decrease the binding of Smad4 in an Argonaute 1-dependent manner. Ectopic expression or knockdown experiments indicated that miR-558 promoted the in vitro and in vivo tumorigenesis and aggressiveness of gastric cancer cell lines via attenuating Smad4-mediated repression of HPSE expression. In clinical gastric cancer specimens, up-regulation of miR-558 and down-regulation of Smad4 were positively correlated with HPSE expression. Kaplan-Meier survival analysis revealed that miR-558 and Smad4 were associated with unfavourable and favourable outcome of gastric cancer patients, respectively. Therefore, these findings demonstrate that miR-558 facilitates the progression of gastric cancer through directly targeting the HPSE promoter to attenuate Smad4-mediated repression of HPSE expression.

| S-EPMC5059886 | biostudies-literature

ErbB2 Pathway Activation upon Smad4 Loss Promotes Lung Tumor Growth and Metastasis.

Project description:Lung cancer remains the leading cause of cancer death. Genome sequencing of lung tumors from patients with squamous cell carcinoma has identified SMAD4 to be frequently mutated. Here, we use a mouse model to determine the molecular mechanisms by which Smad4 loss leads to lung cancer progression. Mice with ablation of Pten and Smad4 in airway epithelium develop metastatic adenosquamous tumors. Comparative transcriptomic and in vivo cistromic analyses determine that loss of PTEN and SMAD4 results in ELF3 and ErbB2 pathway activation due to decreased expression of ERRFI1, a negative regulator of ERBB2 in mouse and human cells. The combinatorial inhibition of ErbB2 and Akt signaling attenuate tumor progression and cell invasion, respectively. Expression profile analysis of human lung tumors substantiated the importance of the ErbB2/Akt/ELF3 signaling pathway as both a prognostic biomarker and a therapeutic drug target for treating lung cancer.

| S-EPMC7405934 | biostudies-literature

PAK3 promotes the metastasis of hepatocellular carcinoma by regulating EMT process.

Project description:Purpose: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. The malignant biological behavior of HCC is closely related to epithelial-mesenchymal transition (EMT), and EMT plays an important role in the progression, migration and metastasis of HCC. P21-activated kinase 3 (PAK3) is a serine/threonine protein kinase, and PAK3 affects the EMT, proliferation, metastasis and invasion of HCC. Methods: In this study, the relationship between PAK3 and HCC was first analyzed by bioinformatics, and then, the expression of PAK3 in clinical samples was detected by immunohistochemistry (IHC), quantitative real-time PCR (qRT-PCR) and Western blotting. Subsequently, the expression of PAK3 was further confirmed in HCC cells. In addition, after the overexpression or knockdown of PAK3 in cells, the proliferation, migration and invasion abilities of these cells were assessed by Cell Counting Kit-8 (CCK-8), wound healing and Transwell assays, and the results were confirmed in vivo experiments in mice. In addition, we also verified that PAK3 affected the EMT and EMT-related pathway of HCC through qRT-PCR, Western blotting and immunofluorescence experiments. Results: Through database analysis, we found that PAK3 was highly expressed in HCC patients and was positively correlated with tumor stage and grade, suggesting that PAK3 expression was closely related to HCC occurrence and development. We subsequently confirmed that PAK3 was overexpressed in HCC clinical samples and HCC cell lines and that PAK3 promoted the proliferation, migration and invasion of HCC cells in vitro. Finally, we found that PAK3 regulated EMT-related molecule expression and EMT-related TGF-β/smad signaling pathway. Conclusion: High expression of PAK3 enhances the invasion of HCC and regulates EMT, suggesting that PAK3 may be a potential target for the treatment of HCC.

| S-EPMC8692680 | biostudies-literature

ErbB2 Pathway Activation upon Smad4 Loss Promotes Lung Tumor Growth and Metastasis [expression]

Project description:Lung cancer remains the leading cause of cancer death. Genome sequencing of lung tumors from patients with Squamous Cell Carcinoma has identified SMAD4 to be frequently mutated. Here we used a novel mouse model to determine the molecular mechanisms regulated by loss of Smad4 which lead to lung cancer progression. Mice with ablation of Pten and Smad4 in airway epithelium developed metastatic adenosquamous tumors. Comparative transcriptomic and in vivo cistromic analyses determined that loss of PTEN and SMAD4 resulted in activation of the ELF3 and the ErbB2 pathway due to decreased ERRFI1 expression, a negative regulator of ERBB2 in mice and human cells. The combinatorial inhibition of ErbB2 and Akt signaling attenuated tumor progression and cell invasion, respectively. Expression profiles analysis of human lung tumors substantiated the importance of the ErbB2/Akt/ELF3 signaling pathway as both prognostic biomarkers and therapeutic drug targets for treating lung cancer. The microarray data includes two different ages of mouse lung samples. The microarray for the study on late stage was did on 12-month-old wild type mouse lungs and Ptend/dSmad4d/d mouse lung tumors. This study was used to identify the significantly changed genes between lung tumors and wild type lungs. The microarray for the study on early stage was did on 7-month-old wild type, Ptend/d and Ptend/dSmad4d/d mouse lungs. This study was used to identify the significantly changed driven genes before the lung tumor initiation and metastasis.

2015-03-05 | E-GEOD-57133 | biostudies-arrayexpress

ErbB2 Pathway Activation upon Smad4 Loss Promotes Lung Tumor Growth and Metastasis [ChIP-seq]

Project description:Lung cancer remains the leading cause of cancer death. Genome sequencing of lung tumors from patients with Squamous Cell Carcinoma has identified SMAD4 to be frequently mutated. Here we used a novel mouse model to determine the molecular mechanisms regulated by loss of Smad4 which lead to lung cancer progression. Mice with ablation of Pten and Smad4 in airway epithelium developed metastatic adenosquamous tumors. Comparative transcriptomic and in vivo cistromic analyses determined that loss of PTEN and SMAD4 resulted in activation of the ELF3 and the ErbB2 pathway due to decreased ERRFI1M-bM-^@M-^Ys expression, a negative regulator of ERBB2 in mice and human cells. The combinatorial inhibition of ErbB2 and Akt signaling attenuated tumor progression and cell invasion, respectively. Expression profiles analysis of human lung tumors substantiated the importance of the ErbB2/Akt/ELF3 signaling pathway as both prognostic biomarkers and therapeutic drug targets for treating lung cancer. Examination of genome-wide SMAD4 binding in 7-month-old Ptend/d mouse lung.

2015-03-05 | E-GEOD-57177 | biostudies-arrayexpress

Downregulation of <i>Let-7</i> miRNA promotes Tc17 differentiation and emphysema via de-repression of RORγt.

Project description:Environmental air irritants including nanosized carbon black (nCB) can drive systemic inflammation, promoting chronic obstructive pulmonary disease (COPD) and emphysema development. The let-7 family of miRNAs is associated with IL-17-driven T cell inflammation, a canonical signature of lung inflammation. Recent evidence suggests the let-7 family is downregulated in patients with COPD, however, whether this repression conveys a functional consequence on emphysema pathology has not been elucidated. Here we show that overall expression of the let-7 miRNA clusters, let-7b/let-7c2 and let-7a1/let-7f1/let-7d, are reduced in the lungs and T cells of smokers with emphysema as well as in mice with cigarette smoke (CS)- or nCB-elicited emphysema. We demonstrate that loss of the let-7b/let-7c2-cluster in T cells predisposed mice to exaggerated CS- or nCB-elicited emphysema. Furthermore, ablation of the let-7b/let-7c2-cluster enhanced CD8+IL17a+ T cells (Tc17) formation in emphysema development in mice. Additionally, transgenic mice overexpressing let-7 in T cells are resistant to Tc17 and CD4+IL17a+ T cells (Th17) development when exposed to nCB. Mechanistically, our findings reveal the master regulator of Tc17/Th17 differentiation, RAR-related orphan receptor gamma t (RORγt), as a direct target of let-7 miRNA in T cells. Overall, our findings shed light on the let-7/RORγt axis with let-7 acting as a molecular brake in the generation of Tc17 cells and suggests a novel therapeutic approach for tempering the augmented IL-17-mediated response in emphysema.

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Loss of canonical Smad4 signaling promotes KRAS driven malignant transformation of human pancreatic duct epithelial cells and metastasis.

Project description:Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer death in North America. Activating KRAS mutations and Smad4 loss occur in approximately 90% and 55% of PDAC, respectively. While their roles in the early stages of PDAC development have been confirmed in genetically modified mouse models, their roles in the multistep malignant transformation of human pancreatic duct cells have not been directly demonstrated. Here, we report that Smad4 represents a barrier in KRAS-mediated malignant transformation of the near normal immortalized human pancreatic duct epithelial (HPDE) cell line model. Marked Smad4 downregulation by shRNA in KRAS (G12V) expressing HPDE cells failed to cause tumorigenic transformation. However, KRAS-mediated malignant transformation occurred in a new HPDE-TGF-β resistant (TβR) cell line that completely lacks Smad4 protein expression and is resistant to the mito-inhibitory activity of TGF-β. This transformation resulted in tumor formation and development of metastatic phenotype when the cells were implanted orthotopically into the mouse pancreas. Smad4 restoration re-established TGF-β sensitivity, markedly increased tumor latency by promoting apoptosis, and decreased metastatic potential. These results directly establish the critical combination of the KRAS oncogene and complete Smad4 inactivation in the multi-stage malignant transformation and metastatic progression of normal human HPDE cells.

| S-EPMC3873993 | biostudies-literature

ErbB2 Pathway Activation upon Smad4 Loss Promotes Lung Tumor Growth and Metastasis [expression]

2015-03-05 | GSE57133 | GEO