Lin-7C/VELI3/MALS-3: An Essential Component in Metastasis of Human Squamous Cell Carcinoma

Abstract

Using proteomic selection, functional verification, and clinical validation, we identified specific down-regulation of Lin-7C/ VELI3/MALS-3 (Lin-7C), which marks oral squamous cell carcinoma (OSCC) metastasis. Despite a rarity of sequence variations in the Lin-7C gene in both primary OSCC and OSCCderived cells, a high prevalence of hypermethylation was detected in the CpG island region that strongly correlated with its down-regulation. Inducible Lin-7C mRNA by experimental demethylation was found in all OSCC cells tested. Overexpression of the Lin-7C gene in an OSCC cell clone does not contribute to underproliferation but results in a noninvasive phenotype with elevated b-catenin expression. Experimental metastases in multiple organs of immunodeficient mice were inhibited in cells expressing Lin-7C. Finally, the Lin-7C expression status in primary tumors afforded significantly (P < 0.001) high accuracy for predicting lymph node metastasis. These results establish Lin-7C as a novel target of early detection, prevention, and therapy for OSCC metastasis.

The Crumbs complex: from epithelial-cell polarity to retinal degeneration

“…Specific downregulation of the expression of LIN-7C was observed in oral squamous-cell-carcinoma-derived cell lines. Re-expression of LIN-7C suppressed not only the invasive behaviour of these cell lines, but also the incidence of experimentally induced metastasis in immunodeficient mice (Onda et al, 2007).…”

Apicobasal polarity and its role in cancer progression

“…Despite the absence of evidence for the epigenetic regulation of core polarity complex proteins, several of their interaction partners show epigenetic alterations in a wide range of cancer types. For example, the down-regulated genes ASPP2 (68) , PTEN (69,70) , APC (71) and Lin-7c (72) display promoter hypermethylation in cancer samples; the protein products of these genes interact with PAR3 (ASPP2 and PTEN), DLG and PALS1, respectively, in normal cells. E-cadherin is also hypermethylated in prostate cancer (71) .…”

“…The Crb3 gene is located at 19p13.3, which also contains several other tumour suppressor genes and is frequently deleted in carcinomas (117) . PALS1 interacts with the PDZ domain protein Lin-7C/VELI3/MALS-3 (Lin-7c) (118) , which is downregulated by promoter hypermethylation in oral squamous cell carcinoma (72) . Finally, sarcoma and lymphoma tumours showed large deletions of PATJ (103) .…”

Dickkopf-1 in human oral cancer

“…To evaluate the effect of Dkk1 knockdown on migration, we performed the wound healing assay described previously (29). Briefly, after uniform wounds were made in confluent culture of shDkk1 and shMock cells, the extent of closure was monitored visually every 4 h for 24 h. The results were visualized by measuring the wound spaces using the Lenalaf220 software (http://www.vector.co.jp/download/file/ win95/art/fh442375.html).…”