Takanobu Yoshimoto

A Homeobox Protein, Prox1, Is Involved in the Differentiation, Proliferation, and Prognosis in Hepatocellular Carcinoma

Purpose: It has been shown that a lymphatic differentiation master gene, prox1, also plays an essential role in fetal hepatocyte migration. Its expression is detected in embryonic hepatoblasts and in adult hepatocytes. Hepatoma cells are similar to embryonic hepatoblasts to a certain extent because they both proliferate and invade the surrounding tissue. To address the possibility that Prox1 may be involved in the tumorigenesis of hepatocellular carcinoma (HCC), human clinical samples were analyzed. Experimental Design: To screen prox1 as a potential tumor suppressor gene, its expression was analyzed in HCC cell lines and in human HCC tissues. Its growth-conferring abilities were assessed by transiently overexpressing Prox1 in HCC cell lines and by knocking down its expression by RNA interference. Results: We found that there was a significant correlation between Prox1 expression and the differentiation scores of the tumors. Subsequently, we also showed that low expression of Prox1 in tumors was closely associated with a poor prognosis. The specific knockdown of Prox1 by RNA interference strongly accelerated in vitro cell growth, whereas the overexpression of Prox1 greatly suppressed the growth. Conclusions: Our results suggest that Prox1 is involved in the differentiation and progression of HCC, and thus it may be a candidate for the development of novel diagnostic and therapeutic strategies for HCC.

Molecular Mechanisms of Lymphangiogenesis

Although the process of vascular development has been well documented, little is understood about lymphatic vasculature formation, despite its importance in normal and pathologic conditions.The dysfunction or abnormal growth of lymphatic vessels is associated with lymphedema and cancer metastasis. The recent discovery of lymphangiogenic growth factors vascular endothelial growth factor (VEGF)-C and VEGF-D and of their receptor,VEGFR-3, on lymphatic endothelial cells has started to provide an understanding of the molecular mechanisms of lymphangiogenesis. In addition, other genes that participate in the specification of lymphatic endothelial cells and the modulation of lymphatic vascular development have been identified. The capacity to induce or inhibit lymphangiogenesis by the manipulation of such molecules offers new opportunities to understand the function of the lymphatic system and to develop novel treatments for lymphatic disorders.This review describes the main players in lymphangiogenesis that have been identified so far and the attempts to shed some light on the mysteries surrounding this process.