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SASH1 is a prognostic indicator and potential therapeutic target in non-small cell lung cancer.

ABSTRACT: SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor protein that has roles in key cellular processes including apoptosis and cellular proliferation. As these cellular processes are frequently disrupted in human tumours and little is known about the role of SASH1 in the pathogenesis of the disease, we analysed the prognostic value of SASH1 in non-small cell lung cancers using publicly available datasets. Here, we show that low SASH1 mRNA expression is associated with poor survival in adenocarcinoma. Supporting this, modulation of SASH1 levels in a panel of lung cancer cell lines mediated changes in cellular proliferation and sensitivity to cisplatin. The treatment of lung cancer cells with chloropyramine, a compound that increases SASH1 protein concentrations, reduced cellular proliferation and increased sensitivity to cisplatin in a SASH1-dependent manner. In summary, compounds that increase SASH1 protein levels could represent a novel approach to treat NSCLC and warrant further study.

SUBMITTER: Burgess JT

PROVIDER: S-EPMC7596716 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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SASH1 is a prognostic indicator and potential therapeutic target in non-small cell lung cancer.

Burgess Joshua T JT Bolderson Emma E Adams Mark N MN Duijf Pascal H G PHG Zhang Shu-Dong SD Gray Steven G SG Wright Gavin G Richard Derek J DJ O'Byrne Kenneth J KJ

Scientific reports 20201029 1

SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor protein that has roles in key cellular processes including apoptosis and cellular proliferation. As these cellular processes are frequently disrupted in human tumours and little is known about the role of SASH1 in the pathogenesis of the disease, we analysed the prognostic value of SASH1 in non-small cell lung cancers using publicly available datasets. Here, we show that low SASH1 mRNA expression is associated with poor surviv ...[more]

PMID: 33122723

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Project description:Hypoxia-inducible factors (HIFs) induced by reduced O2 availability activate the transcription of target genes encoding proteins that play important roles in communication between cancer and stromal cells. Cancer cells were incubated under hypoxic conditions: H1299, A549 (NSCLC); Hep3B, HepG2 (HCC); HCT116, CT26 (Colon cancer); MCF-7, MDAMB231 (Breast cancer); MKN1, MKN5 (Gastric cancer); U87MG, SHSY5Y (Brain cancer); and SKOV3, SNU840 (Ovary cancer). All cells expressed HIF-1α and HIF-2α mRNA and proteins. However, cell proliferation of NSCLC, breast, gastric, and brain cancer cells under hypoxia was more dependent on HIF-1α except for HCC cells where it was more dependent on HIF-2α. Among HIF-1α dependent cells H1299 was the most affected in terms of cell proliferation by HIF-1α knockdown. To examine which cytokines are secreted in NSCLC cells by HIF-1α to communicate with stromal cells, we performed a cytokine-profiling array with H1299. We screened the top 14 cytokines which were dependent on the HIF-1α expression pattern. Among them, midkine (MDK) expression was affected the most in response to HIF-1α. MDK is a heparin-binding growth factor that promotes angiogenesis and carcinogenesis. Indeed, MDK significantly increased HUVEV endothelial cell migration and neo- vascularization in chick chorioallantoic membrane assay (CAM) assay via paracrine signaling. In addition, MDK secreted from NSCLC cells interacted with Notch2 which activated the Notch signaling pathway and induced EMT, upregulated NF-κB, and increased cancer promotion. However, in response to MDK knock down, siRNA or the MDK inhibitor, iMDK treatment not only decreased MDK-induced migration and angiogenesis of endothelial cells but also abrogated the progression and metastasis of NSCLC cells in in vitro and in vivo orthotopic and spontaneous lung metastasis models. Consequently, iMDK treatment significantly increased mice survival rates compared with the control or MDK expression group. MDK plays a very important role in the progression and metastasis of NSCLC cells. Moreover, the MDK targeting strategy provides a potential therapeutic target for the treatment of MDK-expressing lung cancers.

Project description:Abstract Glioma is the most common primary malignant tumor in the brain with extremely poor prognosis. Firstly, in order to find the important genes and mechanisms involved in the initiation and progression of glioma, we selected four groups of gene expression profiles from GEO dataset include GSE29796, GSE4290, GSE50161 and GSE7696 for comprehensive data analysis. We identified 360 differentially expressed genes (DEGs), then we screened out core gene which is CDK1 by protein-protein interaction (PPI) network analysis. So as to clarify whether CDK1 is an independent prognostic factor for glioma, we performed expression analysis and prognostic analysis. Meanwhile, in order to verify the expression and survival of CDK1, we used Western blot to detect CDK1 expression of 15 glioma specimens and corresponding adjacent tissues. Moreover, we divided the expression values of CDK1 gene in the CGGA database into high and low groups based on the median for differential expression analysis. Finally, to explore the molecular mechanism of action of CDK1 in gliomas, we conducted gene ontology (GO) enrichment analysis and gene collection enrichment analysis (GSEA),and performed gene co-expression analysis. The results revealed that the expression level of CDK1 in glioma was significantly higher than normal tissues, its high expression was closely associated with poor survival of glioma. And the prognostic analysis showed that CDK1 was an independent prognostic index of glioma. Through the mechanism analysis of GO and GSEA, it is demonstrated that CDK1 plays an important role in the mitosis cell cycle of glioma, and inhibiting the expression of CDK1 can affect the proliferation of glioma cells. Coexpression analysis displayed that the high expression of PCNA, MCM2, MCM3, MCM4, MCM6, PLK1, TTK and MAD2L1 are also correlated to the poor survival and prognosis of glioma. Hence CDK1 is an independent prognostic factor and potential therapeutic target of glioma. Furthermore ,we can affect the proliferation of glioma cells through inhibiting the expression of CDK1.

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SASH1 is a prognostic indicator and potential therapeutic target in non-small cell lung cancer.

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SASH1 is a prognostic indicator and potential therapeutic target in non-small cell lung cancer.

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