Elsevier

European Journal of Cancer

Volume 50, Issue 12, August 2014, Pages 2142-2151
European Journal of Cancer

Transport and Golgi organisation protein 1 is a novel tumour progressive factor in oral squamous cell carcinoma

https://doi.org/10.1016/j.ejca.2014.05.006Get rights and content

Abstract

Transport and Golgi organisation protein 1 (TANGO), also known as MIA3, belongs to the melanoma inhibitory activity (MIA) gene family. Although MIA acts as an oncogene, MIA2 and TANGO have a tumour-suppressive function in several malignancies; accordingly, the role and function of the MIA gene family in tumours remain controversial. Here the roles of TANGO were investigated in oral squamous cell carcinoma (OSCC). We analysed expression and function of TANGO in human OSCC cell lines. TANGO expression was also examined in 171 cases of primary OSCC by immunohistochemistry and statistically assessed the correlation between TANGO positivity and the clinicopathological parameters including vessel density. By TANGO knockdown in OSCC cells, the growth and invasion were repressed and apoptosis was induced. Activities of platelet-derived growth factor beta polypeptide (PDGFB) and Neuropilin2 were inhibited by TANGO knockdown. TANGO immunoreactivity was detected in 35.1% (60/171) cases of OSCC. TANGO expression was strongly associated with tumour progression, nodal metastasis, clinical stage and number of blood or lymph vessels in OSCC. Patients showing TANGO-expression fared significantly worse disease-free survival than cases without TANGO expression. These findings suggest that TANGO might promote angiogenesis and lymphangiogenesis by upregulation of PDGFB and Neuropilin2 in OSCC.

Introduction

Head and neck cancer, including oral squamous cell carcinoma (OSCC), is the sixth most common malignancy in the world, with an estimated 275,000 cases and 128,000 deaths annually [1], [2]; it is the leading cause of cancer death in Southeast Asia and India [3]. In the United States, OSCCs represent approximately 3.2% of all newly diagnosed cancers each year [4]. In Japan, mortality from OSCC is 3.7 per 100,000 [5]. OSCC has a high potential for local invasion and lymph node metastasis. Over 80% of early-stage OSCCs can be cured by treatment, whereas fewer than 70% of advanced-stage cases can be rescued [6]. Overall 5-year survival rates of OSCC have not significantly improved during the past 30 years, and the 5-year survival rate is less than 50% for all stages [7], [8].

Transport and Golgi organisation protein 1 (TANGO) belongs to the melanoma inhibitory activity (MIA) gene family together with the homologous genes MIA, OTOR and MIA2 [9], [10], [11], [12], [13], [14], [15]. The gene name for TANGO is MIA3. Members of the MIA gene family share 34–45% amino acid homology and 47–59% cDNA sequence homology and have a highly conserved SH3-like structure [10], [12], [13], [14]. The four members also have hydrophobic N-terminal secretory signal sequences [10], [12], [13], [14]. MIA expression is accelerated by high-mobility group box 1 (HMGB1) nuclear factor kappa B (NFkB) p65 complexes binding to the promoter region of the MIA [16], [17]. MIA has been found to be associated with tumour progression in malignant melanoma, gastric cancer, breast cancer, chondrosarcoma, glioma and pancreatic cancer [18], [19], [20], [21], [22], [23], [24], [25]. We also reported that MIA promotes angiogenesis and lymphangiogenesis by activation of the vascular endothelial growth factor (VEGF) family in OSCC [17], [26]. Expression of OTOR is highly restricted in healthy eyes, cochlea and cartilage [27]. MIA2 has a hepatocyte nuclear factor (HNF)-1 binding site, and downregulation of MIA2 was observed in hepatocellular carcinoma (HCC) [9], [11], [15], whereas we found overexpression of MIA2 in OSCC [28]. Higher expression of TANGO was observed during embryogenesis and in many adult tissues, excluding haematopoietic system cells [10], [13]. It has been suggested that TANGO possesses a tumour-suppressive function in malignant melanoma, colorectal cancer (CRC) and HCC [12], [14]. However, the functional role of TANGO in OSCC is still unclear.

Angiogenesis plays a pivotal role in prenatal development, wound healing, chronic inflammation, tumour progression and metastasis; lymphangiogenesis promotes lymph node metastasis in cancer cells [17], [26]. In this study, we investigated the expression and functional role of TANGO, including its role in angiogenesis or lymphangiogenesis. We also confirmed a relationship between TANGO expression and several angiogenic or lymphangiogenic factors, that is, VEGF-A, VEGF-C, VEGF-D [17], [26], [28], [29], platelet-derived growth factor beta polypeptide (PDGFB), FoxC2, Angiopoietin2, Prox1 and Neuropilin2 [30], [31], [32], [33], [34], [35], [36], [37], [38], [39] in OSCC.

Section snippets

Cell culture

Human OSCC cell lines, HSC2, HSC3, HSC4, Ca9-22 and SAT cells, human CRC cells, WiDr and Colo320 cells, human HCC cells, HepG2 and PLC cells and human melanoma cells, HTZ19 cells were used. HSC3 cells have high metastatic potential, HSC4 cells have low metastatic ability and HSC2, Ca9-22 and SAT cells have no ability of metastasis and invasion. All cells were obtained from Health Science Research Resources Bank and maintained in Dulbbeco’s modified Eagle’s medium (DMEM) (Wako Pure Chemical,

Expression and function of TANGO in OSCC cells

At first, five OSCC cells and two cells each of CRC, HCC and melanoma were assessed for MIA and TANGO expression by qRT-PCR. Expression levels of TANGO in OSCC cells were higher than in other cancer cells. HSC3 cells with high metastatic ability showed higher expression of TANGO. HSC2, Ca9-22 and SAT cells that lacked the ability to invade and metastasise showed lower expression (Fig. 1a). We also confirmed that expression levels of TANGO were lower in CRC-derived WiDr and Colo320 cells, and in

Discussion

TANGO is one of the members of the MIA gene family, and it is reported to have a tumour-suppressive role [10], [12], [14], [21]. In the current study, we determined that TANGO regulates migration, invasion, inhibition of apoptosis and expression of PDGFB or Neuropilin2 in OSCC cells. TANGO was also associated with promotion of interaction and transmigration of OSCC cells and vascular or lymphatic vascular endothelial cells. Furthermore, we confirmed that TANGO secreted by OSCC cells promotes

Conflict of interest statement

None declared.

Acknowledgements

This work was supported in part by Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science.

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