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Loss of ZG16 is regulated by miR-196a and contributes to stemness and progression of colorectal cancer.

ABSTRACT: Colorectal cancer (CRC) is one of the most common malignant tumour and the leading cause of cancer-related mortality worldwide. Clarification of the mechanism that underlies CRC tumorigenesis and progression therefore is urgently needed ffor developing novel therapies. Through analysis of The Cancer Genome Atlas (TCGA) dataset, we identified an interesting gene, ZG16, which is significantly decreased in CRC samples compared to adjacent non-tumor tissues and associated with prognosis of patients. We found that the expression of ZG16 correlated with CRC related genes which were regulated by APC/CTNNB1 pathway. Interestingly, the expression of ZG16 was negatively correlated with CRC stem cell marker, LGR5. Overexpression of ZG16 significantly inhibits growth and sphere formation of stem-like CRC cells. Moreover, we also identified an upstream regulator of ZG16, miR-196a, which was significantly overexpressed in CRC and promotes cell growth and stemness. In conclusion, this study demonstrated that loss of ZG16 is regulated by miR-196a and contributes to stemness and progression of CRC, which may provide a promising therapeutic strategy for advanced CRCs.

SUBMITTER: Chen X

PROVIDER: S-EPMC5349946 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Loss of ZG16 is regulated by miR-196a and contributes to stemness and progression of colorectal cancer.

Chen Xiaobing X Du Peng P She Junjun J Cao Liang L Li Yingchao Y Xia Hongping H

Oncotarget 20161201 52

Colorectal cancer (CRC) is one of the most common malignant tumour and the leading cause of cancer-related mortality worldwide. Clarification of the mechanism that underlies CRC tumorigenesis and progression therefore is urgently needed ffor developing novel therapies. Through analysis of The Cancer Genome Atlas (TCGA) dataset, we identified an interesting gene, ZG16, which is significantly decreased in CRC samples compared to adjacent non-tumor tissues and associated with prognosis of patients. ...[more]

PMID: 27880730

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Project description:BackgroundZymogen granule protein 16 (ZG16) is one of the most significantly down-regulated genes in colorectal cancer (CRC) tissues. This study aimed to further evaluate its expression changes and investigate its association with molecular and clinicopathological characteristics of CRC.MethodsWe applied quantitative RT-PCR to determine expression difference between tumor and matched normal tissues from 23 CRC patients. To further validate the down-regulation in tumor tissues, we performed immunohistochemistry (IHC) analysis in 40 paraffin-embedded normal-tumor pairs and 22 colon tissues with a variety of diseases. To evaluate if the ZG16 gene changes were associated with clinicopathological characteristics, we further analyzed the gene expression and copy number changes from The Cancer Genome Atlas (TCGA) and Oncomine datasets.ResultsQuantitative RT-PCR confirmed significant down-regulation (~ 130-fold) of ZG16 in all tumor tissues. ZG16 expression was in an organ-specific manner with an extremely high expression in normal epithelial cells of small intestine, colon and rectum. IHC analysis showed that ZG16 protein was completely lost in all of 40 CRC tissues, and partially lost in premalignant adenomatous polyps (adenomas) and chronic ulcerative colitis tissues. Gene expression and copy number changes were significantly associated with multiple molecular and clinicopathological features of CRC including microsatellite instability (MSI), MLH1 silencing, CpG island methylator phenotype, hyper-mutation status, gender, presence of synchronous adenomas, and histological type (P < 0.05). Patients with lower ZG16 gene expression showed shorter progression-free survival and overall survival than those with relatively higher expression (P < 0.05). Multivariate analysis suggested that the ZG16 expression was an independent prognosis factor (P = 0.012, HR = 6.286, 95% CI = 0.816-0.975).ConclusionFor the first time, our study demonstrated that ZG16 expression was sequentially reduced from normal, adenoma, to carcinoma. Association with multiple clinicopathological features indicates that ZG16 may play an important role in cancer initiation and progression. ZG16 may serve as a potential biomarker for diagnosis and prognosis of CRC.

Project description:BackgroundMetastasis remains the leading cause of mortality among colorectal cancer (CRC) patients. Identification of new metastasis-related genes are critical to improve colorectal cancer prognosis.MethodsData on mRNA expression in metastatic and primary CRC was obtained from the Gene Expression Omnibus (GEO) database, including GSE81986, GSE41568, GSE71222, GSE21510, and GSE14333. Additionally, data concerning mRNA expression in colon cancer (COAD) and adjacent normal tissues were acquired from The Cancer Genome Atlas (TCGA) database. Hub genes were identified by weighted gene co-expression network analysis (WGCNA) and differential gene expression analysis. Moreover, we assessed the impact of hub gene expression on both overall survival (OS) and disease-free survival (DFS) in patients and identified ZG16 as a potential target. We generated CRC cell lines transfected with lentivirus OE-ZG16 to investigate proliferation, invasion, and migration in vitro. To further elucidate the involvement of ZG16, we utilized gene set enrichment analysis (GSEA) to identify enriched pathways, which were subsequently validated via Western blot analysis.ResultsFive datasets containing primary and metastatic CRC samples from GEO database and CRC samples from TCGA database were included in this study and 29 hub genes were identified by WGCNA and differentially expressed gene (DEG) analysis. Low expression of the hub genes (CLCA1 and ZG16) was associated with poor DFS and OS. We confirmed the low expression of ZG16 in CRC using external database and IHC analysis at both transcriptional and protein levels. In addition, the expression of ZG16 was notably elevated in NCM460 cells in comparison to CRC cell lines. The overexpression of ZG16 in CRC cells has been shown to inhibit the proliferation, invasion, and migration of CRC cells. Furthermore, the overexpression of ZG16 has been found to suppress the activation of the epithelial-mesenchymal transition (EMT) and Wnt/β-catenin signaling pathways in CRC.ConclusionZG16 may serve as a promising therapeutic target for metastatic CRC treatment.

Project description:BackgroundCisplatin (DDP) is the first-line chemotherapeutic drug for non-small cell lung cancer (NSCLC), and long-term DDP stimulation increased resistance of NSCLC cells to this drug by enriching cancer stem cells (CSCs), which contributed to recurrence and worse prognosis of NSCLC, but the molecular mechanisms are still not fully delineated.MethodsReal-Time qPCR and Western Blot analysis were conducted to examine gene expressions at mRNA and protein levels, respectively. Dual-luciferase reporter gene system was used to validate the targeting sites among circRNA CDR1as, miR-641 and HOXA9 mRNA. Cell growth was evaluated by CCK-8 assay, trypan blue staining assay and colony formation assay. The Annexin V-FITC/PI double staining method was employed to measure cell apoptosis ratio. Spheroid formation and flow cytometer assay was used to evaluate cell stemness. Xenograft mice models were established to measure tumorgenicity in vivo, and Ki67 expressions in mice tumor tissues were examined by immunohistochemistry (IHC).ResultsHere we identified a novel circRNA CDR1as/miR-641/Homeobox protein Hox-A9 (HOXA9) pathway regulated stemness and DDP chemoresistance in NSCLC. Mechanistically, circRNA CDR1as and HOXA9 were high-expressed, while miR-641 was low-expressed in DDP-resistant NSCLC cells, instead of their corresponding parental DDP-sensitive NSCLC cells. Additionally, we validated that circRNA CDR1as positively regulated HOXA9 in NSCLC cells by serving as an RNA sponge for miR-641, and knock-down of circRNA CDR1as increased the sensitivity of DDP-resistant NSCLC cells, which were reversed by downregulating miR-641 and upregulating HOXA9. Consistently, overexpression of circRNA CDR1as increased drug resistance of DDP-sensitive NSCLC cells by regulating miR-641/HOXA9 axis. In addition, the expression levels of stemness signatures (SOX2, OCT4 and Nanog) were higher in DDP-resistant NSCLC cells, which also tended to form spheres and enrich CD44+CD166+ population compared to their parental DDP-sensitive NSCLC cells, suggesting that CSCs were enriched in DDP-resistant NSCLC cells. Notably, knock-down of circRNA CDR1as inhibited stemness of DDP-resistant NSCLC cells by inhibiting HOXA9 through upregulating miR-641.ConclusionsTaken together, this study identified that circRNA CDR1as regulated stemness and DDP chemoresistance in NSCLC cells by targeting miR-641/HOXA9 axis.

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Loss of ZG16 is regulated by miR-196a and contributes to stemness and progression of colorectal cancer.

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Loss of ZG16 is regulated by miR-196a and contributes to stemness and progression of colorectal cancer.

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