51129

ANGPTL4

angiopoietin-like 4;ANGPTL4;angiopoietin-like 4

PPARG angiopoietin related protein|angiopoietin-related protein 4|fasting-induced adipose factor|hepatic angiopoietin-related protein|hepatic fibrinogen/angiopoietin-related protein|peroxisome proliferator-activated receptor (PPAR) gamma induced angiopoie

19p13.3

protein-coding

Most cases of breast cancer (BrCa) mortality are due to vascular metastasis. BrCa cells must intravasate through endothelial cells (ECs) to enter a blood vessel in the primary tumor and then adhere to ECs and extravasate at the metastatic site. In this study we demonstrate that inhibition of hypoxia-inducible factor (HIF) activity in BrCa cells by RNA interference or digoxin treatment inhibits primary tumor growth and also inhibits the metastasis of BrCa cells to the lungs by blocking the expression of angiopoietin-like 4 (ANGPTL4) and L1 cell adhesion molecule (L1CAM). ANGPTL4 is a secreted factor that inhibits EC-EC interaction, whereas L1CAM increases the adherence of BrCa cells to ECs. Interference with HIF, ANGPTL4 or L1CAM expression inhibits vascular metastasis of BrCa cells to the lungs.

There is strong evidence that the angiopoietin family is involved in the regulation of tumour progression. Recently, it has been reported that angiopoietin-like 4 (ANGPTL4) expression in cancer cells promotes the metastatic process by increasing vascular permeability. The present study was conducted to examine ANGPTL4 expression and its association with clinicopathological factors and prognosis in human colorectal cancers. We examined 144 cases of surgically-resected human colorectal adenocarcinomas by immunohistochemistry, RT-PCR and Western blot analysis. Also, overall survival was investigated. Among 144 cases of adenocarcinoma, 95 cases (66.0%) showed positive staining in the cytoplasm of the carcinoma cells for ANGPTL4. Histologically, well, moderately, poorly differentiated adenocarcinoma or mucinous carcinoma showed 55.2, 79.3, 61.5 or 44.4% expression of ANGPTL4, respectively. The expression of ANGPTL4 was correlated with the depth of tumour invasion (p<0.0005), Vienna classification (category 3-5)(p<0.00005), venous invasion (p<0.0005) and Dukes classification (p<0.005). However, ANGPTL4 expression was not correlated with overall survival. However, all patients (100%) with distant metastasis showed immunopositivity for ANGPTL4. The mRNA and the protein expression of ANGPTL4 were shown in four resected samples and cultured cell lines by RT-PCR or western blot analysis. These findings suggest that ANGPTL4 is one of the factors involved in the progression of human colorectal cancer, especially venous invasion and distant metastasis.

Colorectal cancer (CRC) is one of the most common causes of cancer-related deaths throughout the world. Angiopoietin-like-4 (Angptl4), a member of the angiopoietin family of secreted proteins, is frequently expressed in the perinecrotic areas of different human tumors, yet its role is still unclear in colorectal cancer. Angptl4 mRNA expression in primary colorectal cancer tissue and seven colon cancer cell lines was measured by semi-quantitative RT-PCR; the influence of Angptl4 expression on the colon cancer cell lines was investigated by either overexpression or knockdown of Angptl4 in colon cancer cell lines HCT116 and HT29, respectively. The results showed that Angptl4 mRNA is frequently expressed in human colorectal cancer tissues and cell lines. Overexpression of Angptl4 promoted cell migration, F-actin reorganization and formation of pseudopodia. Further investigation showed that high Angptl4 expression was associated with an increase in ezrin/radixin/moesin and vasodilator-stimulated phosphoprotein expression and a decrease in E-cadherin expression. These results indicate that overexpression of Angptl4 may promote invasion and metastasis in CRC.

There is strong evidence that the angiopoietin family is involved in the regulation of tumour progression, cellular growth and differentiation. Recently, it has been reported that angiopoietin-like 4 (ANGPTL4) in cancer cell promotes the metastatic process by increasing vascular permeability. To elucidate ANGPTL4 expression and its association with clinicopathological factors and prognosis in human gastric adenocarcinomas, we examined 103 cases of surgically-resected human gastric adenocarcinoma by immunohistochemistry. Among 103 cases of adenocarcinoma, 38 cases (36.9%) showed positive staining in the cytoplasm of the carcinoma cells for ANGPTL4. Histologically, papillary and mucinous adenocarcinomas showed relatively high expression of ANGPTL4 (60 and 60%, respectively). The expression of ANGPTL4 was correlated with the depth of tumour invasion (p<0.005), lymph node metastasis (p<0.001), venous invasion (p<0.00005) and TNM stage (p<0.001) in the total carcinoma. In univariate survival analysis, ANGPTL4 expression was not associated with the overall survival. RT-PCR or Western blot analysis showed the expression of mRNA or protein of ANGPTL4 in all four surgically-resected samples and all four cell lines of human gastric adenocarcinoma. ANGPTL4 expression was correlated with several clinicopathological factors, especially venous invasion. These findings suggest that the ANGPTL4 is one of the factors involved in the progression of human gastric cancer.

Angiopoietin-like protein 4 (ANGPTL4) plays complex and often contradictory roles in vascular biology and tumor metastasis, but little is known about its function in hepatocellular carcinoma (HCC) metastasis. In the present study, we showed that hypoxia-inducible factor 1alpha (HIF-1alpha) directly up-regulates ANGPTL4, and its stableness positively correlates with ANGPTL4 expression in HCC tissue. Overexpression of ANGPTL4 significantly increased HCC cell transendothelial migration in vitro and intrahepatic and distal pulmonary metastasis in vivo, whereas silencing ANGPTL4 expression or treatment with a neutralizing antibody specific for ANGPTL4 protein resulted in a reduced transendothelial migration. We also found that serum ANGPTL4 is higher in HCC patients, compared to healthy control, and correlates with intrahepatic metastasis and histological grade. Further, secreted ANGPTL4 promotes transendothelial migration and metastasis of HCC cells in vitro and in vivo through the up-regulation of vascular cell adhesion molecule-1 (VCAM-1) of human umbilical vein endothelial cells and the activation of the VCAM-1/integrin beta1 axis. CONCLUSION: ANGPTL4 is a target gene of HIF-1alpha and acts as an important regulator in the metastasis of HCC. Serum ANGPTL4 correlates with tumor progression and metastasis and might be used to indicate prognosis in HCC patients.