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

// Tomonori Sasahira 1 , Yukiko Nishiguchi 1 , Rina Fujiwara 1 , Miyako Kurihara 1, 2 , Tadaaki Kirita 2 , Anja Katrin Bosserhoff 3 , Hiroki Kuniyasu 1 1 Department of Molecular Pathology, Nara Medical University, Kashihara, Japan 2 Department of Oral and Maxillofacial Surgery, Nara Medical University, Kashihara, Japan 3 Institute of Biochemistry, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany Correspondence to: Tomonori Sasahira, email: sasa@naramed-u.ac.jp Keywords: STOX2, MIA, metastasis, multidrug resistance, oral cancer Received: December 15, 2015 Accepted: March 10, 2016 Published: March 30, 2016 ABSTRACT Background: Storkhead 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. Methods: We used immunohistochemistry and PCR to investigate MIA and STOX2 expression in OSCC. We also performed functional analysis in human OSCC cells. Results: MIA 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. Conclusions: Our results suggest that MIA-STOX2 signaling may be a useful diagnostic and therapeutic target in OSCCs.