Wei-Shu Wang

Overexpression of the thymosin β-4 gene is associated with increased invasion of SW480 colon carcinoma cells and the distant metastasis of human colorectal carcinoma

Cell–matrix and cell–cell adhesive interactions play important roles in the normal organization and stabilization of the cell layer in epithelial tissue. Alterations in the expression and function of these adhesion systems that cause a switch to a migratory phenotype in tumor invasion and metastasis are critical for the malignant conversion of epithelial cells. Thymosin β-4 (Tβ-4) is the major actin-sequestering protein that has been shown to be upregulated in a wide variety of human carcinomas and has been implicated to be involved in altering the motility of certain tumors. We have recently demonstrated that the growth rate, colony formation in soft agar, and motility, all good indicators for malignant progression, of SW480 colon carcinoma cells are dramatically increased by enforced Tβ-4 expression. To test the hypothesis that overexpression of this G-actin sequestering peptide also promotes tumor invasion, we examined not only the invasion capability of Tβ-4-overexpressing SW480 cells, but also the expression levels of Tβ-4 as well as several proteins that participate in different stages of tumor progression in matched samples of human primary colorectal adenocarcinoma and liver metastases from several patients. A marked increase on the invasiveness in Tβ-4-overexpressing SW480 cells with increased levels and activity of matrix metalloproteinase-7 (MMP-7) was observed. Furthermore, the levels of Fas as well as the susceptibility to Fas ligand-mediated apoptosis in Tβ-4-overexpressing cells were significantly decreased. Interestingly, the levels of Tβ-4 mRNA, β-catenin, c-Myc, and MMP-7 in metastatic liver lesions were relatively higher, whereas the levels of E-cadherin and Fas were significantly lower than those in the matched primary colorectal tumors. These results suggest that upregulation of Tβ-4, by promoting the disruption of cell–cell adhesion and a consequential activation of the β-catenin signaling, could be a key event in the acquisition of growth advantages as well as invasive phenotypes in human colorectal carcinomas.

Stevens-Johnson syndrome after treatment with STI571: a case report.

Summary.  Between seven and 21% of patients treated with the specific tyrosine kinase inhibitor STI571 have been reported to develop mild‐to‐moderate severity of adverse cutaneous reactions. We report a patient in the blast crisis phase of chronic myeloid leukaemia who developed a life‐threatening cutaneous reaction, Stevens–Johnson syndrome, following 1 week of STI571 therapy. This report may serve to remind the clinician about the possible severe cutaneous side‐effects of STI571 before instituting more extensive clinical application of this agent in the future.

UGT1A1*28 Polymorphism Predicts Irinotecan-induced Severe Toxicities Without Affecting Treatment Outcome and Survival in Patients With Metastatic Colorectal Carcinoma

It is known that the uridine‐diphosphoglucuronosyl transferase 1A1 (UGT1A1)*28 polymorphism reduces UGT1A1 enzyme activity, which may lead to severe toxicities in patients who receive irinotecan. This study was conducted to assess the influence of this polymorphism on the efficacy and toxicity of irinotecan treatment in Chinese patients with metastatic colorectal carcinoma (CRC).

Thymosin |[beta]|4 triggers an epithelial|[ndash]|mesenchymal transition in colorectal carcinoma by upregulating integrin-linked kinase

The epithelial–mesenchymal transition (EMT) is crucial for the invasion and metastasis of many epithelial tumors including colorectal carcinoma (CRC). In the present study, a scattering and fibroblastic morphology with reduced intercellular contacts was found in the SW480 colon cancer cells overexpressing the gene encoding thymosin β4 (Tβ4), which was accompanied by a loss of E-cadherin as well as a cytosolic accumulation of β-catenin, two most prominent markers of EMT. Whereas E-cadherin downregulation was likely to be accounted by a ZEB1-mediated transcriptional repression, the accumulation of β-catenin was a result of glycogen synthase kinase-3β inactivation mediated by integrin-linked kinase (ILK) and/or its downstream effector, Akt. Intriguingly, ILK upregulation in Tβ4-overexpressing SW480 cells seemed to be attributed mainly to a stabilization of this kinase by complexing with particularly interesting new Cys-His protein (PINCH) more efficiently. In the meantime, a strong correlation between the expression levels of Tβ4, ILK and E-cadherin in CRC patients was also revealed by immunohistochemical analysis. Taken together, these data suggest a novel role of Tβ4 in promoting CRC progression by inducing an EMT in tumor cells via upregulating ILK and consequentially its signal transduction.

Overexpression of the thymosin β -4 gene is associated with malignant progression of SW480 colon cancer cells

Thymosin β-4 (Tβ-4), a small peptide originally isolated from calf thymus, modulates the formation of F-actin microfilaments by sequestering the monomeric G-actin. Recent studies have shown that overexpression of the Tβ-4 gene occurs not only in many human carcinomas but also in the highly metastatic melanomas and fibrosarcomas. However, little is known about the specific growth advantages acquired by different tumors from this genetic abnormality. To address the above questions, Tβ-4-overexpressing human colon carcinoma (SW480) cells were established by stable transfection and their phenotypic changes were monitored. We found that both the morphology and the cortical actin cytoskeleton of SW480 cells were altered by Tβ-4 overexpression. Moreover, both cellular level and that distributed over the intercellular junctions of the E-cadherin were decreased in the Tβ-4 overexpressers, which were accompanied by a twofold increase in their saturation densities. Meanwhile, these cells also exhibited an increased ability to form colonies in soft agar. Interestingly, a dramatic increase of growth rate was detected in the Tβ-4 overexpressers, which might be attributed to an accelerated proliferation induced by c-Myc that was activated by nuclear β-catenin. Finally, a motility increase of these cells was demonstrated by two independent migration assays, which was accompanied by an enhanced focal contact. Taken together, our data suggest that the drastic growth property and motility changes of the SW480 cells overexpressing Tβ-4 gene are due mainly to a deregulated cell–cell adhesion arisen from the downregulation of E-cadherin, plus uncontrolled cell proliferation owing to the upregulation of β-catenin, both resulted from a breakdown of actin microfilaments caused by the overexpression of this G-actin sequestering peptide.

High prevalence of occult hepatitis B virus infection in patients with B cell non-Hodgkin’s lymphoma

Several reports recently found that patients with B cell non-Hodgkin’s lymphoma (NHL) had a higher carrier rate of hepatitis B surface antigen (HBsAg). The current study aimed to examine the hepatitis B virus (HBV) infection status of NHL patients in Taiwan, an HBV-endemic area. Serum HBV and serum hepatitis C virus were measured in 471 NHL patients and 1,013 non-lymphoma cancer patients enrolled between February 2000 and March 2007. Furthermore, nested polymerase chain reaction of HBV-DNA was used to examine the sera from selected patients in these two populations and healthy volunteers for the presence of occult HBV infection. The infection rates (as indicated by the rates of HBsAg and occult HBV) were compared between different groups. There was a higher incidence of HBV infection in B cell NHL patients (23.5%), especially patients with diffuse large B lymphoma, than solid tumor patients (15.6%, P = 0.001). Among HbsAg-negative patients, those with B cell NHL had a higher prevalence of occult HBV infection (6%) than those with non-lymphoma solid tumors and healthy volunteers, 0% and 0.9%, respectively (P = 0.005). B cell NHL patients, even HBsAg-negative B cell NHL patients, but not T cell NHL patients, have a higher incidence of HBV infection than patients with solid tumors. Our findings support the etiologic role of HBV infection in B cell NHL.

Outcome of colorectal carcinoma in patients under 40 years of age

Aims:  Colorectal carcinoma in patients under 40 years of age usually has a poor prognosis. Controversies still exist regarding the features and the prognosis of colorectal cancer in young patients.

Influence of GSTP1 I105V polymorphism on cumulative neuropathy and outcome of FOLFOX-4 treatment in Asian patients with colorectal carcinoma

Glutathione S‐transferase P1 (GSTP1) participates in detoxification of potentially genotoxic compounds that may alter the efficacy and toxicity of platinum‐based chemotherapy. We analyzed the influence of I105V polymorphism of GSTP1 on clinico‐pathological features and outcomes in 166 Chinese patients with metastatic colorectal carcinoma who had been treated with first‐line FOLFOX‐4. Combined analysis of GSTP1 I105V, ERCC1‐118, and XPD‐751 polymorphisms was also conducted. The results showed that, in comparison with Caucasian populations, a remarkably lower prevalence of Val105 allele variants was noted (24.7%). Patients with Val105 allele variants had a higher response to FOLFOX‐4 (56.1%vs 37.6%, P = 0.04), and a longer progression‐free (P < 0.01) as well as overall (P < 0.01) survival. By adjusted analysis, this polymorphism was identified as an independent prognostic factor (P = 0.01). In combined analysis, patients without any risk genotype, including GSTP1‐105 Ile/Ile, ERCC1‐118 C/T or T/T, and XPD‐751 Lys/Gln, had significantly longer progression‐free and overall survivals (P < 0.01). In addition, patients with Val105 allele variants had a higher incidence of grade 3/4 cumulative neuropathy after different cycles of treatment. These data suggest that Asian populations have a lower prevalence of I105V polymorphism in GSTP1. I105V polymorphism in GSTP1, by reducing its enzymatic activity and consequential detoxification to oxaliplatin, could be a key determinant for a better outcome, but more neurotoxicity, to FOLFOX‐4 treatment. (Cancer Sci 2009)

ERCC1 codon 118 C→T polymorphism associated with ERCC1 expression and outcome of FOLFOX‐4 treatment in Asian patients with metastatic colorectal carcinoma

We analyzed the influence of codon 118 C→T polymorphism of ERCC1 on its protein expression levels, clinicopathological features, and outcome of 168 Chinese patients with metastatic colorectal carcinoma that had been treated with first‐line FOLFOX‐4 chemotherapy. A high prevalence of C/C genotype was noted (47.6%, n = 80; 168 patients in total). A marked increase of ERCC1 protein expression levels was also noted in patients with C/T or T/T genotypes (70%vs 20%; P < 0.01), which was associated with significantly lower response to FOLFOX‐4 (36.4%vs 57.5%; p = 0.01), and shorter progression‐free (7 months vs 13 months; P < 0.01) and overall (16 months vs 25 months; P < 0.01) survival times. By multivariate analysis, this polymorphism was also identified as an independent prognostic factor (P = 0.02). These data suggest that Asian populations have a significantly higher prevalence of the C/C genotype in ERCC1 codon 118, which could be a key determinant for good responses to oxaliplatin‐based treatment and favorable outcomes. (Cancer Sci 2009; 100: 278–283)

Colorectal carcinoma: from tumorigenesis to treatment

Abstract.Colorectal carcinoma (CRC) is a complicated and often fatal genetic disease. Fortunately, owing to rapid expansion of knowledge and technology development in oncology, much progress has been made regarding the diagnosis, understanding of the molecular genetics and malignant progression, as well as the novel regimens of CRC. In this review, we summarize the staging system, the most critical genetic and epigenetic alterations, the pleiotropic effects of MMP-7, the controversial roles of Hedgehog signaling, the intriguing involvement of thymosin β-4, and the possible contribution of the putative colon (cancer) stem cells in CRC tumorigenesis. Current treatments as well as several potentially applicable therapeutic strategies for CRC are also discussed.