B7‐H4 facilitates proliferation of esophageal squamous cell carcinoma cells through promoting interleukin‐6/signal transducer and activator of transcription 3 pathway activation

Abstract

B7‐H4, one of the costimulatory molecules of the 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. B7‐H4 silenced cells suppressed cellular proliferation and colony formation. Additionally, compared with control cells, B7‐H4 silenced cells showed higher apoptosis rates, Bcl‐2 and Survivin upregulation, and BAX downregulation. Further study revealed that B7‐H4 silenced cells also showed reduction in interleukin‐6 (IL‐6) secretion, signal transducer and activator of transcription 3 (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. Interleukin‐6 receptor antagonist tocilizumab did not block the p‐JAK2 or p‐STAT3 downregulation induced by B7‐H4 silence. It was suggested that B7‐H4 silence suppressed IL‐6 secretion through JAK2/STAT3 inactivation. Furthermore, cell proliferation and colony formation were downregulated by tocilizumab in control cells but not in B7‐H4 silenced cells, indicating that IL‐6 upregulation induced by B7‐H4 was necessary for cell 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 cell proliferation through promoting IL‐6/STAT3 positive loopback pathway activation.

New checkpoints in cancer immunotherapy

“…B7S1 facilitated ESCC cell proliferation through promoting IL‐6/STAT3 positive loopback pathway activation . B7S1 silencing in ESCC cells reduced IL‐6 secretion, STAT3 activation and p‐STAT3 translocation from cytoplasm to nucleus.…”

“…In a breast cancer cell line, overexpression of B7S1 protected epithelial cells from anoikis, while siRNA‐mediated knockdown of B7S1 mRNA and protein expression increased caspase activity and apoptosis. In the oesophageal squamous cell carcinoma (ESCC), B7S1 silence suppressed cell proliferation and colony formation of ECSC cell lines, in which B7S1 was highly expressed compared with normal esophageal tissue.…”

Prognostic value of association of OCT4 with LEF1 expression in esophageal squamous cell carcinoma and their impact on epithelial‐mesenchymal transition, invasion, and migration

“…The prognosis of ESCC remains poor despite advances in its diagnosis and treatment, even after esophagectomy and lymph node dissection 2. Therefore, a thorough investigation of the cellular and molecular mechanisms that initiate tumorigenesis and promote tumor progression is imperative to provide a better understanding of the medical therapies of ESCC.…”

p‐Hydroxylcinnamaldehyde slows the progression of 4NQO‐induced oesophageal tumourigenesis via the RhoA‐MAPK signaling pathway

“…Cytokine imbalance is an innate immunoregulatory mechanism that contributes to immune suppression and tolerance in various settings . IL‐6 and MIC‐1 derived from ESCC or preneoplastic lesions might play an important role in the suppression of the immune system and growth of ESCC by regulating various signaling pathways such as the PI3 K/Akt or MEK/ERK pathways . The levels of the immune‐promoting cytokines IFN‐γ and TNF‐α were increased, while the levels of the immunosuppressive cytokines sB7‐H4, IL‐6, and MIC‐1 were decreased, in the serum and tissue microenvironment of mice in the CMSP treatment and prevention groups, further suggesting the immune‐promoting function of CMSP in the oesophageal preneoplastic lesion model mice.…”