Downregulation of iNOS/NO Promotes Epithelial-Mesenchymal Transition and Metastasis in Colorectal Cancer
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ABSTRACT:
PROVIDER: PRJNA741254 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14907682_1.fastq.gz | Fastqsanger.gz | |||
| SRR14907682_2.fastq.gz | Fastqsanger.gz | |||
| SRR14907683_1.fastq.gz | Fastqsanger.gz | |||
| SRR14907683_2.fastq.gz | Fastqsanger.gz | |||
| SRR14907684_1.fastq.gz | Fastqsanger.gz |
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Project description:Oleanolic acid (OA) exhibits extensive pharmacological activities and takes significant anti-tumor effects. Its pharmacological mechanism, however, are still remained to be further clarified. In this study, we demonstrated that OA attenuated the migration and invasion abilities, resulting in the suppression of the EMT process in liver cancer cells, and inhibited the tumor growth of the PLC-bearing mice. We further proved that inducible nitric oxide synthase (iNOS) may be the potential target of OA. We confirmed that OA could promote the dimerization of iNOS, activating it and subsequently increasing the production of nitric oxide (NO). Further experiments indicated that OA promoted the nitration of specific proteins and consequently suppressed their epithelial–mesenchymal transition (EMT)-related biological functions. Furthermore, it has been confirmed that OA enhanced the anti-tumor effects of regorafenib in liver cancer treatment. These results deepened our understanding of the pharmacological mechanism of the antitumor effect OA, and the importance of NOS as a therapeutic target for liver cancer treatment.
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Project description:Elevated lipocalin-2 (Lcn2) has been observed in multiple human cancers, but its biological roles remain unclear. Our purpose in this study was to investigate whether Lcn2 is involved in hepatocellular carcinoma (HCC) development via its involvement in invasion and metastasis. Using unsupervised hierarchical clustering analysis of tissue samples, we identified preferential expression of Lcn2 (>2-fold change) in the tumor group (differentiated group) versus the non-tumor group (liver cirrhosis group). LCN2 immunoreactivity was positively correlated with TNM stage (r = 0.194, P = 0.020), but not with differentiation or recurrence of HCC. Over-expression of Lcn2 was observed in HLK-2, HKK-2, and HLK-5 HCC cells. Knock-down of Lcn2 by shRNA in HKK-2 cells was correlated with the down-regulation of E-cadherin, CK-8, CK-18, and desmoplakin I/II (DesI/II) and the up-regulation of N-cadherin, vimentin (VIM), and fibronectin (FN), which are markers of the epithelial-mesenchymal transition (EMT) associated with tumor progression. The characteristics of EMT were reversed by adenoviral transduction of Lcn2 into SH-J1 cells. EGF or TGF-β treatment resulted in downregulation of Lcn2 with a concomitant change in EMT. Stable Lcn2 expression in HCC cells reduced the expression of the transcription factor Twist1, resulting in the inhibition of cell proliferation, migration, and invasion in vitro, and suppressed tumor growth and metastatic ability in a mouse model. These findings suggest that Lcn2 can reverse the EMT in HCC through transcriptional suppression of Twist 1. Thus, Lcn2 is a candidate metastasis suppressor and a potential therapeutic target for HCC. Unsupervised hierarchical clustering separated the samples into two main groups: a non-tumor group (NT, n = 40) and a HCC group (HCC, n = 40), and into two subgroups: a liver cirrhosis group (LC, n = 20) and a differentiated HCC group (difHCC, n = 20). Lcn2 was one of the unique genes with a two-fold or greater difference in expression from the mean with P < 0.01 based on the t-test for hierarchical clustering analysis.
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