B7-H4 facilitates proliferation of esophageal squamous cell carcinoma cells through promoting IL-6/STAT3 pathway activation

Summary

B7-H4, one of the costimulatory molecules of B7 family, has been found to be widely expressed in many kinds of tumor tissues and to play an important part in tumor progression and poor prognosis. However, the role of B7-H4 in esophageal squamous cell carcinoma (ESCC) cells has not been elucidated. In this study, we found that, compared with normal esophageal tissue, B7-H4 was highly expressed in three ESCC cell lines, Eca109, TE1 and TE13. Besides, B7-H4 silence suppressed cells proliferation and colony formation. Additionally, compared with control cells, B7-H4 silence cells showed higher apoptosis rate, Bcl-2 and Survivin upregulation as well as BAX downregulation. Further study demonstrated that B7-H4 silence cells also exhibited reduction of IL-6 secretion, STAT3 activation and p-STAT3 translocation from cytoplasm to nucleus. Moreover, B7-H4 depletion inhibited the IL-6 secretion of control cells but not JAK2/STAT3 inhibitor FLLL32 treated cells. IL-6 receptor antagonist Tocilizumab didn't block the p-JAK2 and p-STAT3 downregulation induced by B7-H4 silence. It was suggested that B7-H4 silence suppressed IL-6 secretion through JAK2/STAT3 inactivation. Furthermore, cells proliferation and colony formation were downregulated by Tocilizumab in control cells but not B7-H4 silence cells demonstrating that IL-6 upregulation induced by B7-H4 was necessary for cells growth. On the other hand, B7-H4 expression was downregulated by Tocilizumab. In all, our study provided the first evidence that B7-H4 facilitated ESCC cells proliferation through promoting IL-6/STAT3 positive loopback pathway activation.

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