Expression of Hugl-1 is strongly reduced in malignant melanoma

Abstract

The human gene Hugl-1 (Llgl/Lgl1) has significant homology to the Drosophila tumor suppressor gene lethal(2)giant larvae (lgl). The lgl gene codes for a cortical cytoskeleton protein, Lgl, that is involved in maintaining cell polarity and epithelial integrity. We speculate that Hugl-1 might play a role in epithelialmesenchymal transition (EMT) and that loss of Hugl-1 expression plays a role in the development or progression of malignant melanoma. Thus, we evaluated melanoma cell lines and tissue samples of malignant melanoma for loss of Hugl-1 transcription. We found that Hugl-1 was downregulated or lost in all cell lines and in most of the tumor samples analysed, and that these losses were associated with advanced stage of the disease. Reduced Hugl-1 expression occurred as early as in primary tumors detected by both immunohistochemical and reverse transcription-polymerase chain reaction (RT-PCR) analysis. Functional assays with stable Hugl-1-transfected cell lines revealed that Hugl-1 expression increased cell adhesion and decreased cell migration. Further, downregulation of MMP2 and MMP14 (MT1-MMP) and re-expression of E-cadherin was found in the Hugl-1-expressing cell clones supporting a role of Hugl-1 in EMT. Our studies thus indicate that loss of Hugl-1 expression contributes to melanoma progression.

Linking epithelial polarity and carcinogenesis by multitasking Helicobacter pylori virulence factor CagA

“…In Drosophila, mutations in the neoplastic tumor suppressor genes, lgl, dlg and scrib, disrupt polarity of epithelia and simultaneously induce overproliferation of epithelial cells with malignant characteristics, indicating the function of the fly tumor suppressors in coupling cell polarity and cell proliferation (Humbert et al, 2003;Bilder, 2004;Humbert et al, this issue). Consistent with this idea, decreased expression of Lgl, Dlg or Scrib is observed in a variety of human tumors (Cavatorta et al, 2004;Nakagawa et al, 2004;Schimanski et al, 2005;Kuphal et al, 2006). Furthermore, Dlg and Scrib are targeted for ubiquitin-mediated degradation by the high-risk human papillomavirus E6 oncoprotein, which is associated with cervical carcinoma, and also by the human T-cell leukemia virus type 1 tax oncoprotein (Kiyono et al, 1997;Lee et al, 1997;Gardiol et al, 1999;Suzuki et al, 1999;Nakagawa and Huibregtse, 2000).…”

aPKCζ cortical loading is associated with Lgl cytoplasmic release and tumor growth in Drosophila and human epithelia

“…Moreover, Hugl-1 shows the same basolateral distribution as the endogenous Lgl and its ectopic expression in a wild-type (wt) background does not perturb epithelial morphogenesis (unpublished data); protein localization might thus be epistatic to protein abundance for these membraneanchored shape determinants, c'est a`dire: no matter how many molecules are available, but they have to stay at the right site to work properly. Hugl-1 deregulation has been associated with several types of epithelial cancers (Grifoni et al, 2004;Schimanski et al, 2005;Kuphal et al, 2006) and several recent papers support a causative role for aPKCi overexpression in carcinomas (Eder et al, 2005;Regala et al, 2005); in the same works, from 'low' to 'almost undetectable' levels of aPKCz have been found in normal and cancer tissues, but in the light of our hypothesis it could play a still secret role in cell polarity and proliferation. An in situ analysis performed on mouse embryo sections also revealed substantial differences in expression between i and z isoforms; the level of aPKCz transcript was on average substantially lower compared to that of aPKCi but often restricted to the epithelial layer of organs (Kovac et al, 2007).…”

Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression

“…Recently, the polarity protein Par6 has been shown to play a critical role during TGFbinduced EMT 33,34 . In addition, loss of Hugl-1 also is associated with EMT in melanoma cells; restoration of expression Hugl-1 restores epithelial cell polarity while also inhibiting cell migration 35 . These studies suggest that cell polarity has a close relationship with the EMT process during the progression of cancer.…”