5629

PROX1

prospero homeobox 1;PROX1;prospero homeobox 1

homeobox prospero-like protein PROX1|prospero homeobox protein 1|prospero-related homeobox 1

1q41

protein-coding

Extensive hypermethylation and consecutive transcriptional silencing of tumorsuppressor genes have been documented in multiple tumor entities including breast cancer. In a microarray based genome-wide methylation analysis of five sporadic breast carcinomas we identified a hypermethylated CpG island within the first intron of the prospero related homeobox gene 1 (PROX1). We, therefore, investigated CpG island methylation of PROX1 in a series of 33 pairs of primary breast cancer and corresponding normal tissue samples by bisulfite sequencing and COBRA analyses. Seventeen of these (52%) breast cancer samples revealed a significant accumulation of methylated CpG sites along with a significant reduction of PROX1 transcription compared to normal breast tissues of the same patients. Frequent methylation was also observed in brain metastases from primary breast cancer (21/37 = 57% of cases). Secondary, we analysed 38 brain metastases of primary breast carcinomas and detected a significantly reduced expression of PROX1 compared to normal breast tissue (p < 0.001) and primary breast carcinomas (p < 0.05), respectively. Additionally, treatment of breast cancer cell lines with demethylating agents could reactivate PROX1 transcription. In summary, we have identified PROX1 as a novel target gene that is hypermethylated and transcriptionally silenced in primary and metastatic breast cancer.

Hepatocellular carcinoma (HCC) is one of the most common cancers and the third leading cause of death from cancer worldwide. HCC has a very poor prognosis because of tumor invasiveness, frequent intrahepatic spread, and extrahepatic metastasis. The molecular mechanism of HCC invasiveness and metastasis is poorly understood. The homeobox protein PROX1 is required for hepatocyte migration during mouse embryonic liver development. In this study, we show that high PROX1 protein expression in primary HCC tissues is associated with significantly worse survival and early tumor recurrence in postoperative HCC patients. Knockdown of PROX1 expression in HCC cells inhibited cell migration and invasiveness in vitro and HCC metastasis in nude mice while overexpression of PROX1 in HCC cells promoted these processes. PROX1's pro-metastasis activity is most likely attributed to its up-regulation of hypoxia-inducible factor 1alpha (HIF-1alpha) transcription and stabilization of HIF-1alpha protein by recruiting histone deacetylase 1 (HDAC1) to prevent the acetylation of HIF-1alpha, which subsequently induces an epithelial-mesenchymal transition response in HCC cells. We further demonstrated the prognostic value of using the combination of PROX1 and HDAC1 levels to predict postoperative survival and early recurrence of HCC. CONCLUSION: PROX1 is a critical factor that promotes HCC metastasis.

OBJECTIVE: To investigate the expression of lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), the homeobox gene (Prox-1), in patients with non-small cell lung cancer (NSCLC), the relationship with microlymphatic vessel density, lymph node metastasis and their clinic pathological value. METHODS: Forty specimens of the NSCLC as experimental group and eleven pulmonary benign diseases as control group were studied. The expressions of LYVE-1, Prox-1 and CD31 protein in specimens of NSCLC and normal pulmonary tissue were studied with immunohistochemical (IHC) technique. Microlymphatic vessel density (MLVD) and microvessel density (MVD) were counted. Meanwhile, all specimens were also examined by conventional pathological method. Clinicopathological data of each patient were recorded and analyzed. RESULTS: (1) Among 40 cases of the center of NSCLC cancerous tissues, the MLVDs marked by LYVE-1 and Prox-1 were 4.22 +/- 1.25 and 1. 99 +/- 1.49 respectively, which were significantly lower than those of the pulmonary benign diseases tissues (P = 0.00). (2) The MLVDs marked by LYVE-1 and Prox-1 in NSCLC cancerous invasive edge were 10.89 +/- 2.06 and 6.63 +/- 1.99 respectively, which were significantly higher than those in the center of cancerous tissues and those of the pulmonary benign diseases tissues (P = 0.000). (3) The MLVDs marked by LYVE-1 and Prox-1 in cancerous invasive edge were not correlated with age, gender, site and dimension of lesion, types of histological and degree of differentiation, but correlated significantly with lymph node metastasis (P = 0.000) and PTNM stage (P = 0.000). Meanwhile, along with lymph node metastasis and increasing of PTNM stage, the expressions of LYVE-1 and Prox-1 protein and MLVDs have significantly increased, but the microvessel density marked by CD31 in cancerous invasive edge was not correlated significantly with lymph node metastasis (P = 0.450) and PTNM stage (P = 0.377). (4) Significant correlation between LYVE-1 and Prox-1 (r = 0.529, P = 0.000) expression was observed in NSCLC; moreover, no correlations between LYVE-1 and CD31, Prox-1 and CD31 (r = 0.034, P = 0.837; r = -0.075, P = 0.647) were The functional microlymphatic vessels correlated with lymphatic metastasis are mainly observed. CONCLUSION: located in the cancerous invasive edge rather than the center of cancerous tissues. LYVE-1 and Prox-1 might be acted as molecular phenotypes of lymphangioghesis in NSCLC and as important markers for evaluating lymphatic metastasis and prognosis in patients with NSCLC.