A multidimensional integration analysis reveals potential bridging targets in the process of colorectal cancer liver metastasis

Gao, Bo; Tian, Yu; Xue, Dongbo; Sun, Boshi; Shao, Qing; Choudhry, Hani; Marcus, Victoria; Ragoussis, Jiannis; Zhang, Yuguo; Zhang, Weihui; Gao, Zu–Hua

doi:10.1371/journal.pone.0178760

Cited by 8 publications

(10 citation statements)

References 56 publications

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“…MiR‐203a was inversely association with both PIK3CG and GNG2 expression, again suggesting a direct association that would operate at the stimulate component of the pathway. Up‐regulation of miR‐203 has been shown to inhibit proliferation and metastasis in CRC . These associations could serve as key targets for future research.…”

Section: Discussionmentioning

confidence: 99%

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The PI3K/AKT signaling pathway: Associations of miRNAs with dysregulated gene expression in colorectal cancer

Slattery

Mullany

Sakoda

et al. 2017

Molecular Carcinogenesis

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The PI3K/AKT-signaling pathway is one of the most frequently activated signal-transduction pathways in cancer. We examined how dysregulated gene expression is associated with miRNA expression in this pathway in colorectal cancer (CRC). We used data from 217 CRC cases to evaluate differential pathway gene expression between paired carcinoma and normal mucosa and identify miRNAs that are associated with these genes. Gene expression data from RNA-Seq and miRNA expression data from Agilent Human miRNA Microarray V19.0 were analyzed. We focused on genes most associated with CRC (fold change (FC) of >1.5 or <0.67) that were statistically significant after adjustment for multiple comparisons. Of the 304 genes evaluated, 76 had a FC of <0.67 and 57 had a FC of >1.50; 47 of these genes were associated with miRNA differential expression. There were 145 mRNA:miRNA seed-region matches of which 26 were inversely associated suggesting a greater likelihood of a direct association. Most miRNA:mRNA associations were with factors that stimulated the pathway. For instance, both IL6R and PDGFRA had inverse seed-region matches with seven miRNAs, suggesting that these miRNAs have a direct effect on these genes and may be key elements in activation of the pathway. Other miRNA:mRNA associations with similar impact on the pathway were miR-203a with ITGA4, miR-6071 with ITGAV, and miR-375 with THBS2, all genes involved in extracellular matrix function that activate PI3Ks. Gene expression in the PI3K/Akt-signaling pathway is dysregulated in CRC. MiRNAs were associated with many of these dysregulated genes either directly or in an indirect manner.

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Section: Discussionmentioning

confidence: 99%

“…Up-regulation of miR-203 has been shown to inhibit proliferation and metastasis in CRC. 43 These associations could serve as key targets for future research.…”

Section: Discussionmentioning

confidence: 99%

The PI3K/AKT signaling pathway: Associations of miRNAs with dysregulated gene expression in colorectal cancer

Slattery

Mullany

Sakoda

et al. 2017

Molecular Carcinogenesis

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“…[ 25 ] Moreover, binding has been noted between transcription factor E2F4 and lncRNA IRX5 or lncRNA FOXF1, which play an important role in colorectal cancer liver metastasis. [ 26 ] In our study, upon LINC00337 upregulation in ESCC cells, binding of E2F4 to TPX2 was enhanced, and consequently, the transcriptional expression of TPX2 was increased. Furthermore, our findings illustrated that TPX2, which is upregulated in ESCC, promoted autophagy and inhibited the chemosensitivity of ESCC cells to DDP.…”

Section: Discussionmentioning

confidence: 50%

Long non‐coding RNA LINC00337 induces autophagy and chemoresistance to cisplatin in esophageal squamous cell carcinoma cells via upregulation of TPX2 by recruiting E2F4

et al. 2020

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Esophageal cancer represents the eighth most frequently occurring cancer, as well as the sixth most widespread cause of cancer-related deaths. In recent years, accumulating evidence has implicated long non-coding RNAs in the progression of esophageal squamous cell carcinoma (ESCC). The aim of the present study was to investigate the potential involvement and underlying mechanisms of LINC00337 in ESCC. Expression patterns of LINC00337 and targeting protein for Xenopus kinesin-like protein 2 (TPX2) in ESCC tissues and cells were detected using RT-qPCR and immunohistochemical staining. Next, the interactions among LINC00337, E2F4, and TPX2 were identified using chromatin immunoprecipitation, dual-luciferase reporter, and RNA-binding protein immunoprecipitation assays, suggesting that LINC00337 could recruit E2F4 to enhance the transcription of TPX2. Thereafter, the regulatory roles of LINC00337 and TPX2 in ESCC were analyzed by altering the expression of LINC00337 or TPX2 in ESCC cells following treatment with cisplatin (DDP). The levels of autophagy-related proteins Beclin1 and LC3II/LC3I, viability, autophagy, apoptosis, and chemoresistance of ESCC cells to DDP were measured following transfection treatment with different plasmids. Additionally, the role of the LINC00337/E2F4/TPX2 axis was assessed in vivo by measuring tumor formation in nude mice. The results demonstrated that LINC00337 upregulated TPX2, consequently leading to elevated levels of Beclin1 and LC3II/LC3I, promoted cell viability and autophagy, while inhibiting apoptosis and chemosensitivity to DDP in ESCC. In sum, the current study evidenced that the overexpression of LINC00337 6056 | YANG et Al.

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“…Overlap gene module between samples of ADM and PanIN was selected by hypergeometric test with following formula [25]: M, n, N and m represents the number of genes in ADM module, PanIN module, STRING database and overlap modules in total respectively. Overlap gene module between samples of PDAC and PanIN was also selected by the formula mentioned above.…”

Section: Overlap Gene Modules Among Adm Panin and Pdacmentioning

confidence: 99%

“…Whether the crosstalk of two gene modules is statistically signi cant depends on the number of interaction between two certain PPI networks and random computation [25]. One pair of sub-network modules of ADM and PanIN (PanIN and PDAC) had m times of participation interaction in actual conditions.…”

Section: Crosstalk Gene Modules Among Adm Panin and Pdacmentioning

confidence: 99%

Gene modules and non-coding RNAs involved in pancreatic tumorigenesis through acinar ductal metaplasia

Zhang

Shi

Gao

et al. 2020

Preprint

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Background Acinar ductal metaplasia (ADM) can progress through pancreatic ductal carcinoma in situ (PanIN) to pancreatic ductal adenocarcinoma (PDAC). However, the genetic alterations and its transcriptional regulators during the process of ADM-driven PDAC tumorigenesis are largely unknown. Therefore, we applied a multidimensional integration strategy to unveil the gene modules and non-coding RNAs that drives the ADM-PanIN-PDAC process. Methods GSE40895 and the microarray datasets were integrated to unmask the regulators link ADM, PanIN and PDAC. Based on the differential expressed genes and protein–protein interaction (PPI) networks for each stage, Overlap and crosstalk gene modules in ADM-PanIN-PDAC were identified using STRING and Cytoscape. Function of these modules were elucidated by gene ontology analysis. Expression level of hub genes and survival analysis were investigated in human PDAC via GEPIA. MiRDB database was applied to predict potential non-coding RNAs (ncRNAs) capable of regulating overlap and crosstalk genes. Results We found several bridging ADM gene modules (e.g. SMARCA1 and H2AFZ), PanIN gene modules (e.g. HDAC11 and SMARCA2) and PDAC gene modules (e.g. OLFR239 and CLIP3). They were enriched in in nucleosome assembly, chromatin organization and G-protein coupled receptor signaling pathway by GO analysis. MicroRNAs (e.g. mmu-miR-335-5p and mmu-miR-669n) and lncRNAs (e.g. H19 and Gm14207) took part in this ample crosstalk by regulating the gene expression. Conclusions SMARCA1, SMARCA2 and CLIP3 were identified as novel crosstalk genes and significant prognostic biomarkers, providing new insights into ADM-driven PDAC carcinogenesis. Transcriptional regulatory non-coding RNAs targeting crosstalk and overlap genes appear promising for early PDAC intervention.

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A multidimensional integration analysis reveals potential bridging targets in the process of colorectal cancer liver metastasis

Cited by 8 publications

References 56 publications

The PI3K/AKT signaling pathway: Associations of miRNAs with dysregulated gene expression in colorectal cancer

The PI3K/AKT signaling pathway: Associations of miRNAs with dysregulated gene expression in colorectal cancer

Long non‐coding RNA LINC00337 induces autophagy and chemoresistance to cisplatin in esophageal squamous cell carcinoma cells via upregulation of TPX2 by recruiting E2F4

Gene modules and non-coding RNAs involved in pancreatic tumorigenesis through acinar ductal metaplasia

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