Overexpression of homeobox geneHOXD3 induces coordinate expression of metastasis-related genes in human lung cancer cells

Abstract

Homeobox-containing genes are expressed in spatiotemporal fashion during embryogenesis and act as master transcription-regulating factors which control the expression of a variety of genes involved in morphogenesis. They are also expressed in a tissue-specific manner in normal adult tissues and appear to give cells spatial information in the maintenance of their architectural integrity. We transfected a HOXD3 class I homeobox-containing gene into human lung cancer A549 cells and investigated alterations in gene expressions and phenotypes related to the maintenance of tissue architecture in HOXD3-overexpressing A549 cells. In the HOXD3-overexpressing cell lines, expression of E-cadherin was lost and plakoglobin was strongly repressed, whereas integrin ␣3 and ␤3 were up-regulated and N-cadherin and integrin ␣4 were newly expressed. Compared with parental and control transfectant lines, the HOXD3-overexpressing cell lines showed highly motile and invasive activity. Blocking experiments using anti-integrin ␤1 and ␤3 suggested that the increased haptotaxis of the HOXD3-overexpressing cells to vitronectin resulted from increased expression and activation of integrin ␣v␤3, and that overexpression of the HOXD3 gene converted the integrin ␤1-dependent haptotaxis to fibronectin into both integrin ␤1-and ␤3-dependent one. HOXD3 overexpression increased production of matrix-degrative enzymes including matrix metalloproteinase-2 and urokinase-plasminogen activator. When the tumor cells were intravenously injected into the tail veins of nude mice, HOXD3 transfectants formed a significantly large number of metastatic foci in lungs compared with the control transfectants. These findings suggest that HOXD3 can act as a metastasis-promoting gene in human lung cancer A549 cells.

Altered expressions of HOX genes in human cutaneous malignant melanoma

“…12 Our previous studies showed that human lung cancer A549 cells transfected with HOXD3 gene acquired more metastatic, invasive and motile phenotypes. 13,14 We also observed that the transduction of HOXD3-antisense expression vectors into human melanoma cells dramatically diminished their invasive and motile activities. 15 Taken together, inappropriate expression of a particular HOX gene(s) is likely involved in tumor development and malignant progression such as invasion and metastasis and that the HOX gene(s) responsible for oncogenesis and/or tumor progression differs according to the organs or tissues from which the tumor cells have derived.…”

The intestine-specific homeobox gene Cdx2 decreases mobility and antagonizes dissemination of colon cancer cells

“…Inversely, HoxD3 increases cell mobility and wound repair, while HoxB13 and Goosecoid promote invasion (Hansen et al, 2003;Zhao et al, 2005;Hartwell et al, 2006;Ohta et al, 2006). The cell spreading effect of HoxD3 correlates with its role in regulating cell-cell and cell-matrix interactions via the stimulation of integrin-a V b3 and reduction of Ecadherin (Hamada et al, 2001;Ohta et al, 2006). Cdx2 plays a key role in intestinal differentiation by upregulating intestinal-specific genes and inhibiting cell proliferation, which may contribute to antagonize cancer cell dissemination.…”

p53 dominant-negative mutant R273H promotes invasion and migration of human endometrial cancer HHUA cells

“…Matrigel invasion assay was performed using a 24-well invasion chamber system (BD Biosciences, Bedford, MA) with Matrigel membrane (8.0-µm pore), as described in our previous report [15]. Briefly, each 750 µl of Ham's F12 medium supplemented with 20% FBS and 10 µg/ml of bovine fibronectin (chemoattractant) was placed in the lower compartment of the chamber.…”