Suppresses Colon Cancer Cell Migration Research Articles

Targeting Colon Cancer Cells with Enzyme-Triggered Casein-Gated Release of Cargo from Mesoporous Silica-Based Nanoparticles.

Colorectal cancer (CRC) is one of the most widely diagnosed cancers worldwide. Despite notable improvements in therapeutic strategies available to CRC patients, late stages of CRC have a higher incidence rate of drug resistance, which is associated with a higher mortality rate. The development of therapeutic strategies that use nanoparticles as a drug delivery system has become one of the most promising potential approaches for cancer therapy. Previous studies have shown that a natural plant alkaloid, veratridine (VTD), suppresses colon cancer cell migration and invasion, two essential factors in tumor metastasis, through activation of the gene that encodes the tumor-suppressor protein UBXN2A. The goal of this study is to develop a nanoassembly to selectively deliver VTD to cancer cells and release it on demand while leaving normal cells intact. We packaged the targeted therapy anticancer molecule VTD inside mesoporous silica nanoparticles (MSNs) impermeable to the blood-brain barrier (BBB) and with selective affinity to CRC cells and sealed the VTD-loaded nanoparticles with an enzymatically cleavable protein. The particles will deliver and release VTD only at the targeted colorectal tumor sites. Since the enzyme MMP-7 protease is dominantly secreted by CRC cells, the release triggered by the enzymes will increase VTD concentration at tumor cells, enhancing the efficiency of the new therapy. We have proven the selective affinity of two types of VTD-carrying particles to CRC cells and enzyme- or acid-triggered VTD release. Negatively surface-charged MSNs showed significant affinity toward positively charged cancer cells but not negatively charged normal fibroblast colon cells, making VTD-MSNs a promising anticancer drug with minimal side effects.

MiR-101 suppresses colon cancer cell migration through the regulation of EZH2.

colorectal cancer (CRC) is one of the most prevalent types of malignancies worldwide. The incidence of CRC is steadily increasing due to extended life expectancy and aging-related genetic and epigenetic abnormalities. Dysregulation of microRNAs (miRNAs) has been implicated in CRC development. the current study is a basic research study aimed at understanding the molecular mechanism of miR-101 in the pathogenesis of CRC using human samples in vivo and CRC cell lines in vitro. The miRNAs profile from human samples was analyzed by miRNA microarrays and the expression level of single miRNAs were confirmed by qRT-PCR. The validation of the direct target of miR-101 was performed by western blot assay. The cell mobility of CRC was assessed using the Transwell migration assay. downregulation of miR-101 was identified in 39 human CRC tissues and CRC cell lines (HT29 and SW620) when compared to their counterpart control. We further confirmed that the enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, is a direct target of miR-101. Overexpression of EZH2 promoted CRC cell line migration and this effect was inhibited by forcing the expression of miR-101. Thus, we conclude that miR-101 regulated colon cancer cell migration occurs at least partially, though targeting EZH2. our study suggests that miR-101 functions as a tumor suppressor in CRC, and miR-101 may be a potential therapeutic target for CRC treatment.

The clinical significance and biological function of tropomyosin 4 in colon cancer

Tropomyosin 4 (TPM4) has been found to be dys-regulated, and function as oncogene or anti-oncogene in human cancers. However, there was no report on the clinical significance and biological function of TPM4 in colon cancer. This study was designed to investigate the clinical value and biological function of TPM4 in colon cancer. Thus, we detected the TPM4 expression in colon cancer clinical samples, and conducted the gain-of-function in colon cancer cell lines. In our results, TPM4 mRNA and protein expressions were reduced in colon cancer tissues and cell lines compared with normal colon tissues and colon epithelial cell line, respectively. TPM4 protein low-expression was obviously associated with clinical stage, T classification (invasion depth), N classification (lymph node metastasis), distant metastasis and differentiation. Survival analysis showed low-expression of TPM4 was an unfavorable independent prognostic factor for colon cancer patients. Moreover, the experiments in vitro suggested up-regulated TPM4 expression suppressed colon cancer cell migration, invasion and metastasis-associated gene expression including MMP-2, MMP-9 and MT1-MMP, but had no effect on cell proliferation. In conclusion, TPM4 is associated with clinical progression in colon cancer patient and acts as a tumor suppressor in colon cancer cell.

Ursolic Acid Simultaneously Targets Multiple Signaling Pathways to Suppress Proliferation and Induce Apoptosis in Colon Cancer Cells

Ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid distributed in medical herbs, exerts antitumor effects and is emerging as a promising compound for cancer prevention and therapy, but its excise mechanisms of action in colon cancer cells remains largely unknown. Here, we identified the molecular mechanisms by which UA inhibited cell proliferation and induced apoptosis in human colon cancer SW480 and LoVo cells. Treatment with UA led to significant inhibitions in cell viability and clone formation and changes in cell morphology and spreading. UA also suppressed colon cancer cell migration by inhibiting MMP9 and upregulating CDH1 expression. Further studies showed that UA inhibited the phosphorylation of Akt and ERK proteins. Pretreatment with an Akt or ERK-specific inhibitor considerably abrogated the proliferation inhibition by UA. UA also significantly inhibited colon cancer cell COX-2 expression and PGE2 production. Pretreatment with a COX-2 inhibitor (celecoxib) abrogated the UA-induced cell proliferation. Moreover, we found that UA effectively promoted NF-κB and p300 translocation from cell nuclei to cytoplasm, and attenuated the p300-mediated acetylation of NF-κB and CREB2. Pretreatment with a p300 inhibitor (roscovitine) abrogated the UA-induced cell proliferation, which is reversed by p300 overexpression. Furthermore, UA treatment induced colon cancer cell apoptosis, increased the cleavage of PARP, caspase-3 and 9, and trigged the release of cytochrome c from mitochondrial inter-membrane space into cytosol. These results indicate that UA inhibits cell proliferation and induces apoptosis in colon cancer cells through simultaneous modulation of the multiple signaling pathways such as MMP9/CDH1, Akt/ERK, COX-2/PGE2, p300/NF-κB/CREB2, and cytochrome c/caspase pathways.

MicroRNA-19a targets tissue factor to inhibit colon cancer cells migration and invasion

The over-expression of tissue factor (TF) and its roles in colon cancer progression have attracted much attention. However, the mechanisms regulating TF expression have not yet been shown in detail. In this study, we over-expressed miR-19a, miR20a and miR-106b in colon cancer cells, and evaluated their impact on TF expression and cellular function. We provide evidence demonstrating that miR-19a inhibited TF expression in vitro. Luciferase reporter assay confirmed that TF was a direct target of miR-19a because the miR-19a mediated repression of luciferase activity was abolished by mutation of the putative binding site. Moreover, miR-19a suppressed colon cancer cell migration and invasion. This effect was due to the indirect down-regulation of matrix metalloproteinase 9. Finally, we investigated the relevance of TF and miR-19a expression in a total of 48 paired colon cancer samples and revealed that miR-19a was inversely correlated with TF expression in stages I and II cases. Therefore, our results suggested that miR-19a was capable of suppressing TF expression in vitro and inhibiting cell migration and invasion. Although it was not the unique mechanism responsible for the expression of TF in vivo, miR-19a was inversely correlated with TF expression in early stage colon cancer patients.

MiRNA-22 suppresses colon cancer cell migration and invasion by inhibiting the expression of T-cell lymphoma invasion and metastasis 1 and matrix metalloproteinases 2 and 9

Emerging evidence has demonstrated the altered expression of mRNAs in cancer development and progression. In this study, the precise role of miRNA-22 (miR-22) in colon cancer cells was investigated. Upon transfection with a miR-22 expression vector, the viability of HCT-116 human colon cancer cells was significantly reduced and tumor cell migration and invasion capacity were also suppressed. Computational in silico analysis predicted that T-cell lymphoma invasion and metastasis 1 (TIAM1) is a target gene of miR-22. This was confirmed by qRT-PCR and western blotting, which showed that miR-22 expression inhibited TIAM1 mRNA and protein expression, respectively. In addition, the expression of pro-invasive gene matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) and pro-angiogenic protein vascular endothelial growth factor (VEGF) were also reduced by miR-22 expression. Collectively, these data suggest that miR-22 may act as a tumor suppressor in colon cancer, most likely by targeting TIAM1 expression.

Tyrosine phosphatase PTPRD suppresses colon cancer cell migration in coordination with CD44

PTPRD is a receptor-type tyrosine-protein phosphatase. Recent analyses of comprehensive mutations and copy numbers have revealed that PTPRD is frequently mutated and homozygously deleted in various types of cancer, including glioblastoma, melanoma, breast and colon cancer. However, the molecular functions of PTPRD in cancer progression have yet to be elucidated. Herein, PTPRD suppressed colon cancer cell migration and was required for appropriate cell-cell adhesion. In addition, PTPRD regulated cell migration in cooperation with β-catenin/TCF signaling and its target CD44. Furthermore, expression levels of PTPRD were down-regulated in highly invasive cancers and were significantly correlated with patient survival. Our findings suggest that PTPRD is required for colon cancer invasion and progression.