TANGO is a tumor suppressor of malignant melanoma

Abstract

The TANGO gene was originally identified as a new family member of the melanoma inhibitory activity gene family. The gene codes for a 14 kDa protein of so far unknown function. In our study we revealed that TANGO was downregulated or lost in 9 melanoma cell lines when compared to normal melanocytes and in most of the 8 tumor samples analyzed. The losses were associated with advanced stage of the disease. These results were confirmed in situ by immunohistochemistry on 10 paraffin-embedded sections of human malignant melanoma primary tumors and melanoma skin metastases. A small reduction of TANGO was also seen in different benign and atypical nevi when compared to normal skin. For functional analysis of TANGO we evaluated TANGO reexpressing melanoma cell clones and antisense TANGO cell clones with a complete loss of TANGO. Functional assays with TANGO transfected or treated cell lines revealed that TANGO expression reduces motility, whereas reduction of TANGO enhances migration. Our studies, therefore, indicate that reduction of TANGO expression contributes to tumor progression. These results taken together provide the first indications for a tumor suppressor role of TANGO gene in human malignant melanoma. ' 2006 Wiley-Liss, Inc.Key words: TANGO; tumor-suppressor gene; migration; malignant melanoma; cancer Malignant melanoma arises from melanocytic cells of the skin and belongs to the most aggressive types of cancer. Malignant melanoma develops when the melanocytes no longer respond to normal control mechanism of cellular growth and are capable of invasion locally or spreading to other organs in the body. Several processes involved in tumor development are known today but detailed molecular changes of this disease are still under investigation.Recent data indicated that loss of cell-cell and cell-matrix contacts, induction of growth factor expression and deregulation of signaling pathways are involved in early development of the disease. 1-3A novel human gene (TANGO) encoding a melanoma inhibitory activity (MIA) homologous protein was identified by a gene bank search.4 TANGO, together with the homologous genes MIA, OTOR (FPD, MIAL) and MIA 2, defines a novel gene family sharing important structural features, significant homology at both the nucleotide and protein level and similar genomic organization. TANGO encodes a mature protein of 103 amino acids in addition to a hydrophobic secretory signal sequence. Sequence homology confirms the highly conserved SH3 structure present also in MIA, OTOR and MIA2. 5,6 Interestingly, in situ hybridization, RT-PCR and Northern Blots revealed very broad TANGO expression patterns in contrast to the highly restricted expression patterns previously determined for the other members of the MIA gene family. High levels of TANGO expression were observed both during embryogenesis and in adult tissues. The only cells lacking TANGO expression are cells belonging to the hematopoietic system. 4 The present study was performed to evaluate the role of TANGO in human tumor development and pro...

Validation of the Association of Genetic Variants on Chromosome 9p21 and 1q41 With Myocardial Infarction in a Japanese Population

“…MIA3, also referred to as ARNT or TANGO, belongs to the melanoma inhibitory activity gene family and may have a role in tumor suppression. 24,25 As with the case of rs1333049, the classic risk factors appear not to be related to the increased MI risks associated with rs17465637.…”

Reduced expression of TANGO in colon and hepatocellular carcinomas

“…We initiated this study because we recently found that TANGO is reduced in malignant melanoma and has a tumor suppressor role in this kind of tumor (14). Specifically, we were interested whether TANGO plays a similar role also in other tumors and, therefore, analyzed the expression of TANGO in colon carcinoma and HCC and whether treatment with TANGO may change the migratory and invasive activity of the colon and hepatoma tumor cells.…”

“…The evaluation of the staining was performed semiquantitatively by light-microscopy. The method was described elsewhere (14).…”

“…Migration and invasion assays were performed using Boyden Chambers containing polycarbonate filters with 8 μm pore size (Costar, Bodenheim, Germany), essentially as described previously (14). Filters were coated with gelatine or matrigel (diluted 1:3 in H 2 O; Becton Dickinson, Heidelberg, Germany), respectively.…”

“…The present study was performed to evaluate the expression pattern of TANGO in colon and hepatoma carcinoma starting from our recently published study on TANGO in malignant melanoma, in which we present that TANGO is a tumor suppressor and could be used as a prognostic marker of progression in melanoma patients (14). Therefore, we screened the expression profiles of TANGO in three hepatoma cell lines (HepG2, HepB3 and PLC) and in six colon carcinoma cell lines (HT29, LoVo, CaCo-2, HCT116, SW480 and SW48), in ten different liver tumor samples in situ and in different colon and hepatoma tumor immunohistological sections.…”