Reduced expression of Hugl-1, the human homologue of Drosophila tumour suppressor gene lgl, contributes to progression of colorectal cancer

Abstract

The human gene, human giant larvae (Hugl-1/Llg1/Lgl1) has significant homology to the Drosophila tumour suppressor gene lethal(2)giant larvae (lgl). The lgl gene codes for a cortical cytoskeleton protein, Lgl, that binds Myosin II and is involved in maintaining cell polarity and epithelial integrity. The human protein, Hugl-1 contains several conserved functional domains found in Lgl, suggesting that these proteins may have closely related functions. Whether loss of Hugl expression plays a role in human tumorigenesis has so far not been extensively investigated. Thus, we evaluated tumour tissues from 94 patients undergoing surgery for colorectal cancer (CRC) for loss of Hugl-1 transcription and compared our findings with the clinical data from each of these patients. We found that Hugl-1 was lost in 75% of tumour samples and these losses were associated with advanced stage and particularly with lymph node metastases. Reduced Hugl-1 expression during the adenoma-carcinoma sequence occurring as early as in colorectal adenomas was detected by both immunohistochemical and reverse transcriptionpolymerase chain reaction analysis. Functional assays with ecdysone-inducible cell lines revealed that Hugl-1 expression increased cell adhesion and decreased cell migration. Our studies thus indicate that downregulation of Hugl-1 contributes to CRC 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).…”

Transcriptional regulation of cell polarity in EMT and cancer

“…Other recent data have shown decreased expression of DLG and/or SCRIB in colorectal tumours, associated with the lack of epithelial cell polarity and a disorganized tissue architecture (Gardiol et al, 2006), as well as in other tumour types (reviewed by Dow and Humbert, 2007). Decreased LGL1 expression has also been reported in several tumours, including colorectal carcinomas (Schimanski et al, 2005), endometrial carcinomas (Tsuruga et al, 2007) or melanomas (Kuphal et al, 2006). In several cases, the downregulation of LGL1 is associated with more advanced stages of the tumour, lymph node metastasis and/or poor survival, supporting its use as a marker of poor prognosis.…”

Basolateral junctions are sufficient to suppress epithelial invasion during Drosophila oogenesis

“…In general, BLJ proteins are conserved in vertebrate epithelia (Knust, 2002), and several BLJ proteins are lost in invasive carcinomas (Fogar et al, 1997;Roesler et al, 1997;Perl et al, 1999;Bazzoni, 2003;Huang et al, 2003;Schimanski et al, 2005). hDlg-1, which directly interacts with the most commonly mutated protein in colorectal cancer, APC, is lost in murine invasive ovarian cancer (Huang et al, 2003), and loss of human ortholog of lgl contributes to colorectal cancer invasion (Schimanski et al, 2005). Greater than 90% of cancers are of epithelial origin, but usually do not pose a serious threat to life until tumor cells start to invade.…”