Chuangyu Wen

Hsa-miR-19a is associated with lymph metastasis and mediates the TNF-α induced epithelial-to-mesenchymal transition in colorectal cancer

Lymph node metastasis is an important factor determining the outcome of colorectal cancer. Although epithelial-to-mesenchymal transition (EMT), TNF-α and microRNA (miRNA) have been found to play important roles in lymph node metastasis, the underlying molecular mechanism remains unclear. Here we reported that high expression of microRNA-19a (miR-19a) was associated with lymph node metastasis and played an important role in TNF-α-induced EMT in colorectal cancer (CRC) cells. We analyzed miR-19a expression in surgical tissue specimens from 11 CRC patients and 275 formalin-fixed, paraffin-embedded CRC patients. We found that miR-19a was up-regulated in CRC tissues and high expression of miR-19a was significantly associated with lymph node metastasis. We further analyzed miR-19a lymph node metastasis signature in an external validation cohort of 311 CRC cases of the TCGA. MiR-19a was found to be significantly associated with lymph node metastasis in rectal cancer. In vitro, we showed that overexpression of miR-19a in human CRC cell lines promoted cell invasion and EMT. Furthermore, miR-19a was up-regulated by TNF-α and miR-19a was required for TNF-α-induced EMT and metastasis in CRC cells. Collectively, miR-19a played an important role in mediating EMT and metastatic behavior in CRC. It may serve as a potential marker of lymph node metastasis.

Gambogic acid inhibits growth, induces apoptosis, and overcomes drug resistance in human colorectal cancer cells

The emergence of chemoresistance is a major limitation of colorectal cancer (CRC) therapies and novel biologically based therapies are urgently needed. Natural products represent a novel potential anticancer therapy. Gambogic acid (GA), a small molecule derived from Garcinia hanburyi Hook. f., has been demonstrated to be highly cytotoxic to several types of cancer cells and have low toxicity to the hematopoietic system. However, the potential role of GA in colorectal cancer and its ability to overcome the chemotherapeutic resistance in CRC cells have not been well studied. In the present study, we showed that GA directly inhibited proliferation and induced apoptosis in both 5-fluorouracil (5-FU) sensitive and 5-FU resistant colorectal cancer cells; induced apoptosis via activating JNK signaling pathway. The data, therefore, suggested an alternative strategy to overcome 5-FU resistance in CRC and that GA could be a promising medicinal compound for colorectal cancer therapy.

TACC3 promotes colorectal cancer tumourigenesis and correlates with poor prognosis

Colorectal carcinoma (CRC) is a malignant epithelial tumour with tremendous invasion and metastatic capacity. Transforming acidic coiled-coil protein-3 (TACC3), a frequently aberrantly expressed oncogene, is an important biomarker in various human cancers. Our study aimed to investigate the expression and function of TACC3 in human CRC. We found that TACC3 was over-expressed at both the mRNA and protein levels in CRC cells and in biopsies of CRC tissues compared with normal controls as determined by qRT-PCR, western blot and immunohistochemical (IHC) staining assays. IHC staining of samples from 161 patients with CRC also revealed that TACC3 expression was significantly correlated with clinical stage (P = 0.045), T classification (P = 0.029) and M classification (P = 0.020). Multivariate analysis indicated that high TACC3 expression was an independent prognostic marker for CRC. Patients who had high TACC3 expression had significantly poorer overall survival (OS, P = 0.023) and disease-free survival (DFS, P = 0.019) compared to patients who had low TACC3 expression. Furthermore, TACC3 knockdown attenuated CRC cell proliferation, colony formation capability, migration and invasion capability, and tumourigenesis in nude mice; these properties were measured using a real-time cell analyser (RTCA), clonogenicity analysis, and transwell and xenograft assays, respectively. These data indicate that TACC3 promotes CRC progression and could be an independent prognostic factor and a potential therapeutic target for CRC.

Thymidine phosphorylase expression and prognosis in colorectal cancer treated with 5‑fluorouracil‑based chemotherapy: A meta‑analysis

In the past decades, various studies have suggested a possible link between thymidine phosphorylase (TP) level and colorectal cancer (CRC) treated with 5-fluorouracil (5-FU)-based chemotherapy; however, they have arrived at inconsistent results. Therefore, the present meta-analysis aimed to disclose a more comprehensive evaluation of this relationship. PubMed, the Cochrane Library, Ovid MEDLINE, Embase and China National Knowledge Infrastructure were systematically searched for studies that evaluated the prognostic value of TP in CRC. Stata 12.0 software was used to test the heterogeneity and evaluate the overall test performance. A total of 15 studies, including 1,225 patients, were included. The summary estimates of TP for CRC treated with 5-FU-based chemotherapy indicated a moderately positive prognosis with a hazard ratio (HR) of 0.76 (P=0.031) for overall survival and a HR of 0.711 (P=0.022) for relapse-free survival. On the basis of the present meta-analysis, TP could be promising and meaningful in the prognosis of CRC treated with 5-FU-based chemotherapy.

PEAK1, acting as a tumor promoter in colorectal cancer, is regulated by the EGFR/KRas signaling axis and miR-181d

PEAK1 is upregulated in multiple human malignancies and has been associated with tumor invasion and metastasis, but little is known about the role of PEAK1 in colorectal cancer (CRC) progression. We investigated the expression pattern, function and regulatory mechanisms of PEAK1 in CRC. Here, we found that PEAK1 is overexpressed in CRC tissues and that high PEAK1 expression predicts poor survival in colon cancer but not rectal cancer. Functionally, silencing PEAK1 inhibits cell proliferation, migration, and invasion in vitro and inhibits the growth of tumor xenografts in nude mice. Mechanistic studies revealed that PEAK1 is induced by epidermal growth factor receptor (EGFR) signaling and that PEAK1 is required for KRas-induced CRC cell growth and metastasis. Furthermore, we demonstrated that miR-181d directly targets PEAK1. Ectopic expression of miR-181d reduces the expression of PEAK1 and inhibits the growth and metastasis of CRC cells in vitro. Clinically, miR-181d is downregulated in CRC samples, and low miR-181d is correlated with poor patient survival. Our study demonstrates the importance of PEAK1 in CRC progression and suggests a potential mechanism by which increasing PEAK1 expression in CRC might be the result of EGFR/KRas signal activation and consequent miR-181d repression.

A novel long noncoding RNA OECC promotes colorectal cancer development and is negatively regulated by miR-143-3p

Emerging evidence indicates that aberrant long non-coding RNA (lncRNA) expression contributes to CRC pathogenesis. To explore the biological functions of lncRNAs in CRC and to identify the underlying mechanisms, we first conducted a lncRNA microarray assay to investigate lncRNA expression patterns in CRC. We identified a novel lncRNA OECC, originating from chromosome 8q24 that is highly expressed in CRC tissues and cell lines and has a positive correlation with liver metastasis. Attenuation of lncRNA OECC expression prohibited CRC cell proliferation, induced apoptosis, and inhibited migration. Furthermore, an inverse correlation between lncRNA OECC and miR-143-3p was observed. Bioinformatic analyses predicted, and a luciferase reporter assay demonstrated, that lncRNA OECC is a direct target of miR-143-3p, leading to down-regulation in the expression of its target genes, the NF-κB and p38 MAPK pathways. Taken together, our results suggest that lncRNA OECC is overexpressed in CRC and may play an oncogenic role through NF-κB and p38 MAPK pathway activation via miR-143-3p.

Toosendanin induces caspase-dependent apoptosis through the p38 MAPK pathway in human gastric cancer cells

Although many advances have been made in the treatment of gastric cancer (GC), numerous difficulties, such as the emergence of chemo-drug resistance, continue to lead to disappointing GC prognoses. Thus, novel alternative strategies are urgently needed. The use of natural products could be a viable option to treat GC. Toosendanin (TSN) is a triterpenoid derived from the bark of Melia toosendanin Sieb. et Zucc that has been shown to be highly cytotoxic to multiple cancer cells. As the underlying impact of TSN on GC and its molecular mechanism remain poorly understood, in this study, we performed a series of experiments involving the use of TSN to treat GC cells. In the present study, we showed that TSN suppressed cell viability, inhibited cell proliferation by causing G1/S arrest and induced caspase-dependent apoptosis in AGS and HGC-27 cells. The possible mechanism of TSN-induced apoptosis may be associated with the activation of the p38 MAPK pathway. These results demonstrated the potential of TSN as a promising therapeutic compound to treat gastric cancer.