GLI1 activation by non-classical pathway integrin αvβ3/ERK1/2 maintains stem cell-like phenotype of multicellular aggregates in gastric cancer peritoneal metastasis

Dong, Hui; Hongchang, Liu; Zhou, Wen; Zhang, Fan; Li, Chuan; Tan, Chenjun; Tang, Bo; Yu, Ping

doi:10.1038/s41419-019-1776-x

Cited by 18 publications

(17 citation statements)

References 47 publications

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“…In previous researches, a large number of studies have elucidated the MAPK signaling, focal adhesion pathway, cGMP-PKG signaling pathway and etc. were closely or partially related to peritoneal metastasis of GC (63)(64)(65)(66)(67). Similar to the findings, the present study observed that 214 genes positively associated with PRIs enriched mainly in MAPK and focal adhesion pathway (Figure 5A), suggesting the major role of these two pathways taking on the peritoneal relapse of GC.…”

Section: Discussionsupporting

confidence: 89%

Immune Landscape of Gastric Carcinoma Tumor Microenvironment Identifies a Peritoneal Relapse Relevant Immune Signature

Zhang

et al. 2021

Front. Immunol.

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BackgroundGastric cancer (GC) still represents the third leading cause of cancer-related death worldwide. Peritoneal relapse (PR) is the most frequent metastasis occurring among patients with advanced gastric cancer. Increasingly more evidence have clarified the tumor immune microenvironment (TIME) may predict survival and have clinical significance in GC. However, tumor-transcriptomics based immune signatures derived from immune profiling have not been established for predicting the peritoneal recurrence of the advanced GC.MethodsIn this study, we depict the immune landscape of GC by using transcriptome profiling and clinical characteristics retrieved from GSE62254 of Gene Expression Omnibus (GEO). Immune cell infiltration score was evaluated via single-sample gene set enrichment (ssGSEA) analysis algorithm. The least absolute shrinkage and selection operator (LASSO) Cox regression algorithm was used to select the valuable immune cells and construct the final model for the prediction of PR. The receiver operating characteristic (ROC) curve and the Kaplan-Meier curve were used to check the accuracy of PRIs. Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to explore the molecular pathways associated with PRIs.ResultsA peritoneal recurrence related immune score (PRIs) with 10 immune cells was constructed. Compared to the low-PRIs group, the high-PRIs group had a greater risk. The upregulation of the focal adhesion signaling was observed in the high-PRIs subtype by GSEA and KEGG. Multivariate analysis found that both in the internal training cohort and the internal validation cohort, PRIs was a stable and independent predictor for PR. A nomogram that integrated clinicopathological features and PRIs to predict peritoneal relapse was constructed. Subgroup analysis indicated that the PRIs could obviously distinguish peritoneal recurrence in different molecular subtypes, pathological stages and Lauren subtypes, in which PRIs of Epithelial-Mesenchymal Transitions (EMT) subtype, III-IV stage and diffuse subtype are higher respectively.ConclusionOverall, we performed a comprehensive evaluation of the immune landscape of GC and constructed a predictive PR model based on the immune cell infiltration. The PRIs represents novel promising feature of predicting peritoneal recurrence of GC and sheds light on the improvement of the personalized management of GC patients after surgery.

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Section: Discussionsupporting

confidence: 89%

Immune Landscape of Gastric Carcinoma Tumor Microenvironment Identifies a Peritoneal Relapse Relevant Immune Signature

Zhang

et al. 2021

Front. Immunol.

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“…In GC, its expression is significantly higher in metastatic cancer tissues and is positively correlated with a more aggressive tumor phenotype . Furthermore, it has been observed that GLI1 overexpression promotes a CSC phenotype enhancing cell proliferation, migration and therapy resistance (Dong et al, 2019;Yao et al, 2019). GLI1 also plays an important role in CSC characteristics related with aggressiveness and metastatic spread of CRC cells leading to decreased survival.…”

Section: Gli1 (Gli Family Zinc Finger 1)mentioning

confidence: 99%

The Relevance of Transcription Factors in Gastric and Colorectal Cancer Stem Cells Identification and Eradication

Pádua

Figueira

Ribeiro

et al. 2020

Front. Cell Dev. Biol.

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Gastric and colorectal cancers have a high incidence and mortality worldwide. The presence of cancer stem cells (CSCs) within the tumor mass has been indicated as the main reason for tumor relapse, metastasis and therapy resistance, leading to poor overall survival. Thus, the elimination of CSCs became a crucial goal for cancer treatment. The identification of these cells has been performed by using cellsurface markers, a reliable approach, however it lacks specificity and usually differs among tumor type and in some cases even within the same type. In theory, the ideal CSC markers are those that are required to maintain their stemness features. The knowledge that CSCs exhibit characteristics comparable to normal stem cells that could be associated with the expression of similar transcription factors (TFs) including SOX2, OCT4, NANOG, KLF4 and c-Myc, and signaling pathways such as the Wnt/βcatenin, Hedgehog (Hh), Notch and PI3K/AKT/mTOR directed the attention to the use of these similarities to identify and target CSCs in different tumor types. Several studies have demonstrated that the abnormal expression of some TFs and the dysregulation of signaling pathways are associated with tumorigenesis and CSC phenotype. The disclosure of common and appropriate biomarkers for CSCs will provide an incredible tool for cancer prognosis and treatment. Therefore, this review aims to gather the new insights in gastric and colorectal CSC identification specially by using TFs as biomarkers and divulge promising drugs that have been found and tested for targeting these cells.

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“…Developing Gli-targeted approach has its merit because of the fact that Gli proteins can be activated by both SHh liganddependent and -independent mechanisms. Gli1 and Gli2 inhibitor include GANT 61 [30] and Arsenic Trioxide [31] that have shown potent inhibition of Gli1 and Gli2 in many cancer cell lines, one of these is GC cells. Currently, many preclinical studies and clinical trials are being conducted to evaluate the efficacy of this exciting class of targeted therapy in a variety of cancers.…”

Section: Discussionmentioning

confidence: 99%

Gli1 regulates stemness characteristics in gastric adenocarcinoma

Yang

Feng

et al. 2020

Diagn Pathol

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Background: Glioma-associated oncogene homolog 1 (Gli1), affects the progression and the stemness characteristics of malignant carcinoma. The aim of the present study was to identify the relation between Gliomaassociated oncogene homolog 1 (Gli1) and stemness and determine its clinical significance in gastric adenocarcinoma (GA). We investigated Gli1 expression and its correlation with other stemness-associated proteins in 169 GA samples and 5 GA cell lines. Methods: To elucidate the role of Gli1 in the clinicopathological significance and stemness of GA, tissues samples from 169 GA patients were collected for immunohistochemistry (IHC). Additionally, MKN74, MKN28, NCI-N87, SNU638, AGS cells were collected for western blotting, MKN28 cells were collected for spheroid formation assay. Results: Results showed that Gli1 expression was closely related to tumor grade, primary tumor (pT) stage, distant metastasis, clinical stage, gross type, microvessel density, and shorter overall survival (OS). Cox regression analysis verified that Gli1 was an independent prognostic factor for OS. Furthermore, Gli1 expression correlated with the expression of stemness-related genes, CD44, LSD1, and Sox9. Gli1 inhibitor GANT61 significantly decreased the expression of CD44 and LSD1, and spheroid formation ability of the MKN28 cells. Conclusions: In conclusion, Gli1 may be a poor prognostic indicator and a potential cancer stemness-related protein in GA.

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GLI1 activation by non-classical pathway integrin αvβ3/ERK1/2 maintains stem cell-like phenotype of multicellular aggregates in gastric cancer peritoneal metastasis

Cited by 18 publications

References 47 publications

Immune Landscape of Gastric Carcinoma Tumor Microenvironment Identifies a Peritoneal Relapse Relevant Immune Signature

Immune Landscape of Gastric Carcinoma Tumor Microenvironment Identifies a Peritoneal Relapse Relevant Immune Signature

The Relevance of Transcription Factors in Gastric and Colorectal Cancer Stem Cells Identification and Eradication

Gli1 regulates stemness characteristics in gastric adenocarcinoma

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