Storkhead box 2 and melanoma inhibitory activity promote oral squamous cell carcinoma progression

Abstract

BackgroundStorkhead box protein 2 (STOX2) is a transcriptional factor associated with pre-eclampsia with fetal growth restriction. We recently reported that melanoma inhibitory activity (MIA) promotes oral squamous cell carcinoma (OSCC) progression. However, the relationship between STOX2 and MIA remains unknown in malignancies.MethodsWe used immunohistochemistry and PCR to investigate MIA and STOX2 expression in OSCC. We also performed functional analysis in human OSCC cells.ResultsMIA and STOX2 mRNA levels were higher in OSCCs than in normal oral epithelial cells, and upregulation of STOX2 was significantly correlated with overexpression of MIA. Immunostaining for STOX2 was associated with nodal metastasis (P = 0.0002) and MIA expression (P < 0.0001). Furthermore, MIA expression (P = 0.0035) and STOX2 expression (P = 0.0061) were associated with poor outcome in OSCCs. In vitro analysis using OSCC cells revealed that MIA increased expression of STOX2 by paracrine manner. Moreover, STOX2 accelerated OSCC cell growth, invasion, suppressed apoptosis, and enhanced resistance to paclitaxel, cisplatin, and 5-FU.ConclusionsOur results suggest that MIA-STOX2 signaling may be a useful diagnostic and therapeutic target in OSCCs.

The importance of melanoma inhibitory activity gene family in the tumor progression of oral cancer

“…The gene expression levels of MIA were higher in the OSCC samples than in the normal oral mucosa . The expression of MIA was also higher in the invasive OSCC than in the carcinoma in situ .…”

“…We previously reported that the melanoma inhibitory activity ( MIA ) gene family is involved in the tumor progression of OSCC . The members of the MIA gene family are secreted proteins that comprise MIA, MIA2, transport and Golgi organization protein 1 (TANGO or MIA3), and otoraplin (OTOR or fibrocyte‐derived protein and MIA‐like) .…”

“…In terms of downstream signal molecules, MIA was observed to be regulated in a paracrine manner by the activation of storkhead box protein 2 (STOX2) and was associated with the acquisition of resistance to anticancer drugs in the OSCC cells . Although STOX2 is known to be involved in the susceptibility to preeclampsia with intrauterine growth restriction, the role of STOX2 in human tumors is not completely understood.…”

“…Although STOX2 is known to be involved in the susceptibility to preeclampsia with intrauterine growth restriction, the role of STOX2 in human tumors is not completely understood. In OSCC, we determined that STOX2 promoted cell growth, inhibited apoptosis, enhanced multidrug resistance, and contributed to nodal metastasis and poor survival, and that STOX2 expression was an independent predictor of disease‐free survival . Therefore, the MIA–STOX2 signaling pathway may be an important route for tumor progression and metastasis in OSCC.…”

“…Globally, head and neck cancer, including oral squamous cell carcinoma (OSCC), is the sixth most common malignancy and has been estimated to account for 529,500 new incident cases and 292,300 deaths annually, representing about 3.8% of all cancer cases and 3.6% of the cancer deaths . In 2017, 49,670 new cases and 9,700 deaths from OSCC were projected to occur in the United States, and the number of deaths due to OSCC per 100,000 individuals was 3.7% in Japan . The sites of predilection for OSCC include the tongue, lower lip, floor of the mouth, gingiva, buccal mucosa, and palate.…”