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

AbstractSMAD4 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 KrasG12D, p53fl/fl LOF and Smad4fl/fl LOF mutations (SPK), showing a much higher incidence of tumor metastases than the KrasG12D, p53fl/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.

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

10.1101/2021.04.29.441956 ◽

2021 ◽

Author(s):

Xiaohong Tan ◽

Lu Tong ◽

Lin Li ◽

Jinjin Xu ◽

Shaofang Xie ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Metastasis ◽

Inverse Correlation ◽

Underlying Mechanism ◽

Human Lung Cancer ◽

Mirna Regulation ◽

Loss Of Function ◽

Lung Cancer Patients ◽

Lung Cancer Metastasis ◽

Potential Marker

AbstractOver 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.

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DT-13 attenuates human lung cancer metastasis via regulating NMIIA activity under hypoxia condition

Oncology Reports ◽

10.3892/or.2016.4879 ◽

2016 ◽

Vol 36 (2) ◽

pp. 991-999 ◽

Cited By ~ 14

Author(s):

Xiao-Hui Wei ◽

Sen-Sen Lin ◽

Yang Liu ◽

Ren-Ping Zhao ◽

Ghulam Jilany Khan ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Metastasis ◽

Human Lung ◽

Human Lung Cancer ◽

Lung Cancer Metastasis

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Inhibition of human lung cancer metastasis using antiplatelet drug and sialidase

Lung Cancer ◽

10.1016/0169-5002(91)91408-4 ◽

1991 ◽

Vol 7 ◽

pp. 17

Keyword(s):

Lung Cancer ◽

Cancer Metastasis ◽

Human Lung ◽

Human Lung Cancer ◽

Antiplatelet Drug ◽

Lung Cancer Metastasis

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Novel pleiotropic effects of bioactive phospholipids in human lung cancer metastasis

Oncotarget ◽

10.18632/oncotarget.17461 ◽

2017 ◽

Vol 8 (35) ◽

pp. 58247-58263 ◽

Cited By ~ 12

Author(s):

Gabriela Schneider ◽

Zachariah Payne Sellers ◽

Kamila Bujko ◽

Sham S. Kakar ◽

Magda Kucia ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Metastasis ◽

Human Lung ◽

Pleiotropic Effects ◽

Human Lung Cancer ◽

Lung Cancer Metastasis

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In-vitro Pre-Treatment of Cancer Cells with TGF-β1: A Novel Approach of Tail Vein Lung Cancer Metastasis Mouse Model for Anti-Metastatic Studies

Current Molecular Pharmacology ◽

10.2174/1874467212666190306165703 ◽

2019 ◽

Vol 12 (4) ◽

pp. 249-260 ◽

Cited By ~ 8

Author(s):

Ghulam Jilany Khan ◽

Li Sun ◽

Muhammad Abbas ◽

Muhammad Naveed ◽

Talha Jamshaid ◽

...

Keyword(s):

Lung Cancer ◽

Mouse Model ◽

Cancer Metastasis ◽

Human Lung ◽

A549 Cells ◽

Human Lung Cancer ◽

Lung Cancer Metastasis ◽

Pre Treatment ◽

Tgf Β1

Background: Aggressive behavior of tumor metastasis comes from certain mutations, changes in cellular metabolic and signaling pathways that are majorly altered by tumor microenvironment (TME), its other components and growth factors like transforming growth factor-β1 (TGF-β1) which is chiefly known for its epithelial to mesenchymal transformation (EMT). EMT is a critical step of metastasis cascade in actual human lung cancer scenario. Objective: Our present study is focused on unveiling the in-vivo metastatic behavior of TGF-β1 treated lung cancer cells that undergo EMT. Methods: The lung cancer epithelial A549 cells were treated in-vitro with TGF-β1 (3-5ng/ml for 72 h) for EMT. After confirming the transformation of cells by phenotype modifications, wound healing and cell migration assay and qRT-PCR analyses of EMT biomarkers including E. Cadherin, Vimentin, Snail, Slug, MMP2 and MMP9; those TGF-β1 modified cells were probed with fluorescent trackers and were injected into the tail vein of BALB/c nude mice for metastatic dissemination studies. Results: Our findings indicate that the distribution of TGF-β1 treated A549 cells as compared to W.T A549 towards lungs is less in terms of total relative fluorescent cluster count, however, the difference is insignificant (52±4, 60±5 respectively). Additionally, we show that TGF-β1 treated cells tend to metastasize almost 2, 3, 1.5, 2 and 1.7 times more than W.T towards liver, brain, ovaries, bones and adrenal gland, respectively, which is very much like human lung cancer metastasis. Conclusion: Conclusively, it is the first study ever reporting that a pre-treatment of cells with TGF-β1 for experimental lung cancer metastasis mouse model may portray a more precise approach for the development of potential therapeutic treatments. Additional pre-treatment studies with the application of other TME conditions like hypoxia and factors like NFκB, VEGF etc. may be a future prospect to develop a better understanding.

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A Case and Review of Bowel Perforation Secondary to Metastatic Lung Cancer

The American Surgeon ◽

10.1177/000313480507100204 ◽

2005 ◽

Vol 71 (2) ◽

pp. 110-116 ◽

Cited By ~ 20

Author(s):

Robert A. Garwood ◽

Mark D. Sawyer ◽

E.J. Ledesma ◽

Eugene Foley ◽

Jeffrey A. Claridge

Keyword(s):

Lung Cancer ◽

Small Bowel ◽

Cell Carcinoma ◽

Cancer Metastasis ◽

Bowel Perforation ◽

Large Cell Carcinoma ◽

Metastatic Lung Cancer ◽

Small Bowel Perforation ◽

Lung Cancer Metastasis ◽

Metastatic Lung

Gastrointestinal tract perforation (GITP) secondary to metastatic lung cancer is extremely rare. We present a case of small bowel perforation secondary to metastatic lung cancer. The objective of this study was to review the current literature and further characterize the incidence, histology, and risk of GITP secondary to lung cancer metastasis. A Medline search was done to identify all the cases of GITP attributed to metastatic lung cancer reported in the literature. Data was collected and analyzed from a collection of cases in the medical literature since 1960. We identified 98 cases of perforated lung cancer metastasis to the small intestine. Four gastric perforations, three colonic perforations, and one appendiceal perforation were also identified but not analyzed. The mean age was 64.5 years. There was a male predominance of 89 per cent versus 11 per cent female. Perforations occurred most often in the jejunum (53%) followed by ileum (28%). Combined jejunum-ileum lesions accounted for 4 per cent of perforations. No duodenal perforations were reported, though a specific site was not determined in 13 per cent of cases. Small bowel perforations were most often caused by adenocarcinoma (23.7%), squamous cell carcinoma (22.7%), large cell carcinoma (20.6%), and small cell carcinoma (19.6%). The prevalence of small bowel perforation secondary to a given primary lung cancer histology varied by region. The mean survival was 66 days with 50 per cent of patients not surviving past 30 days. Despite a high incidence of lung cancer, small bowel perforation secondary to lung cancer metastasis remains relatively rare. Perforated metastases occur more often in men and are found more commonly in the jejunum. Small bowel perforations are caused most often by adenocarcinoma; however, squamous cell and large cell carcinoma metastases are more likely to result in perforation. Small bowel perforation in this setting has a significant impact on mortality, decreasing 1-year survival to less than 3 per cent.

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Human Lung Fibroblasts Inhibit Non-Small Cell Lung Cancer Metastasis in Ex Vivo 4D Model

The Annals of Thoracic Surgery ◽

10.1016/j.athoracsur.2015.05.014 ◽

2015 ◽

Vol 100 (4) ◽

pp. 1167-1174 ◽

Cited By ~ 6

Author(s):

Dhruva K. Mishra ◽

Steven D. Compean ◽

Michael J. Thrall ◽

Xin Liu ◽

Erminia Massarelli ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cancer Metastasis ◽

Human Lung ◽

Ex Vivo ◽

Small Cell ◽

Lung Fibroblasts ◽

Small Cell Lung ◽

Human Lung Fibroblasts ◽

Lung Cancer Metastasis

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Long Non-Coding RNA CRYBG3 Promotes Lung Cancer Metastasis via Activating the eEF1A1/MDM2/MTBP Axis

International Journal of Molecular Sciences ◽

10.3390/ijms22063211 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3211

Author(s):

Anqing Wu ◽

Jiaxin Tang ◽

Ziyang Guo ◽

Yingchu Dai ◽

Jing Nie ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Metastasis ◽

Major Barrier ◽

Lung Cancer Metastasis ◽

Non Coding Rna ◽

Metastatic Lung ◽

Associated Proteins ◽

Underlying Mechanisms ◽

Patient Prognosis

The occurrence of distant tumor metastases is a major barrier in non-small cell lung cancer (NSCLC) therapy, and seriously affects clinical treatment and patient prognosis. Recently, long non-coding RNAs (lncRNAs) have been demonstrated to be crucial regulators of metastasis in lung cancer. The aim of this study was to reveal the underlying mechanisms of a novel lncRNA LNC CRYBG3 in regulating NSCLC metastasis. Experimental results showed that LNC CRYBG3 was upregulated in NSCLC cells compared with normal tissue cells, and its level was involved in these cells’ metastatic ability. Exogenously overexpressed LNC CRYBG3 increased the metastatic ability and the protein expression level of the metastasis-associated proteins Snail and Vimentin in low metastatic lung cancer HCC827 cell line. In addition, LNC CRYBG3 contributed to HCC827 cell metastasis in vivo. Mechanistically, LNC CRYBG3 could directly combine with eEF1A1 and promote it to move into the nucleus to enhance the transcription of MDM2. Overexpressed MDM2 combined with MDM2 binding protein (MTBP) to reduce the binding of MTBP with ACTN4 and consequently increased cell migration mediated by ACTN4. In conclusion, the LNC CRYBG3/eEF1A1/MDM2/MTBP axis is a novel signaling pathway regulating tumor metastasis and may be a potential therapeutic target for NSCLC treatment.

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Identification of Primary and Metastatic Lung Cancer-Related lncRNAs and Potential Targeted Drugs Based on ceRNA Network

Frontiers in Oncology ◽

10.3389/fonc.2020.628930 ◽

2021 ◽

Vol 10 ◽

Author(s):

Siyao Dong ◽

Cheng Wu ◽

Chengyan Song ◽

Baocui Qi ◽

Lu Liu ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Progression ◽

Regulatory Networks ◽

Cancer Metastasis ◽

Lung Squamous Cell Carcinoma ◽

Close Correlation ◽

Therapeutic Effects ◽

Lung Cancer Metastasis ◽

Metastatic Lung ◽

Specific Association

Lung cancer metastasis is the leading cause of poor prognosis and death for patients. Long noncoding RNAs (lncRNAs) have been validated the close correlation with lung cancer metastasis, but few comprehensive analyses have reported the specific association between lncRNA and cancer metastasis, especially via both competing endogenous RNA (ceRNA) regulatory relationships and functional regulatory networks. Here, we constructed primary and metastatic ceRNA networks, identified 12 and 3 candidate lncRNAs for lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) respectively and excavated some drugs that might have potential therapeutic effects on lung cancer progression. In summary, this study systematically analyzed the competitive relationships and regulatory mechanism of the repeatedly dysregulated lncRNAs in lung cancer carcinogenesis and metastasis, and provided a new idea for screening potential therapeutic drugs for lung cancer.

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