TRAF3-interacting protein 3, a new oncotarget, promotes tumor growth in melanoma

Abstract

TRAF3-interacting protein 3 (TRAF3IP3) is expressed in the immune system and participates in cell maturation, tissue development, and immune response. In a previous study, we reported that TRAF3IP3 levels were substantially increased in the vasculature of breast cancer tissues, suggesting a proangiogenic role. In this study, we investigated TRAF3IP3 tumorigenic function. TRAF3IP3 protein was present in several cancer cell lines, with highest levels in melanoma. In addition, tumor microarray analysis on 23 primary melanoma and nine positive lymph nodes revealed that 70% of human primary melanoma and 66% of lymph node metastases were positive for TRAF3IP3. Importantly, TRAF3IP3 downregulation correlated with an 83% reduction of tumor growth in a subcutaneous xenograft mouse model (n=10, P=0.005). Immunohistochemistry analysis of the tumors revealed that TRAF3IP3-shRNA tumors had increased apoptosis (n=4, P<0.01) and reduced microvascular density (n=4, P<0.002). In addition, TRAF3IP3 downregulation in malignant endothelial cells reduced tube formation in a Matrigel tube formation assay. In melanoma cells, decreased levels of TRAF3IP3 were also associated with reduced viability (n=4, P=0.03) and proliferation (n=3, P=0.03), together with increased sensitivity to ultraviolet-induced apoptosis (n=4, P=0.0004). Furthermore, TRAF3IP3 downregulation correlated with increased amounts of interferon-γ. Interferon-γ inhibits tumor growth and angiogenesis, thus suggesting a new pathway for TRAF3IP3 in cancer. Collectively, the association of TRAF3IP3 with malignant properties of melanoma suggest a clinical potential for targeted therapy.

Integrated analysis of dysregulated long non-coding RNAs/microRNAs/mRNAs in metastasis of lung adenocarcinoma

“…TRAF3IP3 is expressed in the immune system and participates in cell maturation, tissue development, and immune response. Nasarre et al [43] identified new functions of TRAF3IP3 in melanoma and angiogenesis, emphasizing its physiological relevance as a potential target for cancer therapy.…”

High TRAF3IP3 Level Predicts Poor Prognosis of Patients with Gliomas

“…Previous studies had shown that TRAF3IP3 was highly expressed in the vascular system of breast cancer tissue specimens, suggesting that TRAF3IP3 may be involved in the occurrence and development of breast cancer [9]. Nasarre P, et al [10]found that the expression of TRAF3IP3 in malignant melanoma primary lesion and lymph node metastases were up-regulated by microarray analysis. Then they found that down-regulation of TRAF3IP3 expression in tumor cells could promote apoptosis of tumor cells, and decrease the density of microvascular.…”

Proteomic Landscape of Cholangiocarcinomas Reveals Three Different Subgroups According to Their Localization and the Aspect of Non‐Tumor Liver

“…The label‐free quantitative proteomic analysis identified tumor necrosis factor receptor–associated factor 3 interacting protein 3 (TRAF3IP3) as the most upregulated protein in iCC C (×11.61; p = 7.5e −4 ). This protein, involved in the activation of the c‐Jun NH2‐terminal kinase (JNK) pathway, is mostly expressed in immune systems as well as in several human malignancies . Although tumor cells may de novo express TRAF3IP3, a substantial increase in TRAF3IP3 has been described in vessels from breast cancers .…”

“…This protein, involved in the activation of the c-Jun NH2-terminal kinase (JNK) pathway, is mostly expressed in immune systems as well as in several human malignancies. [27,28] Although tumor cells may de novo express TRAF3IP3, a substantial increase in TRAF3IP3 has been described in vessels from breast cancers. [27] Given the magnitude of TRAF3IP3 expression observed here in iCC C , its expression might be diffuse in tumor samples, involving not only tumor cells but also endothelial cells as this iCC subgroup demonstrates increased MVD.…”