Abstract
The costimulatory signals CD28 and B7 have been shown to control tumor invasion and metastasis by regulating T cell activation, whereas the distribution characteristics of B7-associated proteins in laryngeal carcinoma (LC) tissue are still unclear. Here, the expression of members of the B7 superfamily, including B7-H1 (PD-L1), B7-DC (PD-L2) and B7-H4, in fifty-two LC samples was determined by immunohistochemistry, and the relationship between B7-H4 and epithelial-mesenchymal transition (EMT)-associated markers was further assessed by immunofluorescence double staining. Furthermore, the human LC cell lines, Hep-2 and TU212 cells, were further transfected to overexpress B7-H4, and cell invasion and metastasis were analyzed. The results showed that B7-H1, B7-DC and B7-H4 were expressed in the tumor cells, and their expression was restricted to the cell membrane and the cytoplasm. The positive rates of these molecules in the tumor tissues were 57.7% (30/52), 32.7% (17/52) and 34.6% (18/52), respectively. Interestingly, double immunofluorescence staining showed that B7-H4 is coexpression with EMT-related markers, including p-Smad2/3, Snail and Vimentin, in carcinoma cells. Moreover, overexpression of B7-H4 in Hep-2 cells promotes the expression of pSmad2/3 and Snail by activating AKT-STAT3 signaling. Transwell and wound-healing assays demonstrated that B7-H4 enhanced both Hep-2 and TU212 cell invasion and metastasis. Our results suggest that B7-H4 transmits feedback signaling to tumor cells and promotes invasion and metastasis by promoting EMT progression. Therefore, blocking B7-H4 signaling might be a novel treatment strategy for LC.
Highlights
Laryngeal carcinoma (LC), which is derived from epithelial cells and accounts for 0.8% of all new cancer cases, is the 14th most common cancer among men [1]
The expression of members of the B7 superfamily, including B7-H1 (PD-L1), B7-DC (PDL2) and B7-H4, in fifty-two laryngeal carcinoma (LC) samples was determined by immunohistochemistry, and the relationship between B7-H4 and epithelial-mesenchymal transition (EMT)associated markers was further assessed by immunofluorescence double staining
The results showed that B7-H1, B7-DC and B7-H4 were expressed in the tumor cells, and their expression was restricted to the cell membrane and the cytoplasm
Summary
Laryngeal carcinoma (LC), which is derived from epithelial cells (the most common squamous cell) and accounts for 0.8% of all new cancer cases, is the 14th most common cancer among men [1]. According to GLOBOCAN, LC caused 83376 deaths in 2012 (3880 in the USA and 12308 in China), and males are much more susceptible to LC than females (10550 new cases in males compared to 2880 females in 2015) [1]. The development of LC is racial biased, with African Americans presenting higher incidence rates and mortality compared with Caucasians [3]. Significant advancements have been made over the www.impactjournals.com/oncotarget past several decades in the treatment of LC. The 5-year survival rate of LC patients has decreased from 66% to 63% over the past 40 years, even though the overall incidence has declined [4]. It is critical to explore the pathogenic and prognostic indicators of LC due to the fact that the molecular tests have not influenced LC treatment selection until now
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