Semaphorin 4D is a potential biomarker in pediatric leukemia and promotes leukemogenesis by activating PI3K/AKT and ERK signaling pathways

Oncol Rep. 2021 Apr;45(4):1. doi: 10.3892/or.2021.7952. Epub 2021 Mar 2.

Abstract

Semaphorin 4D (Sema4D) is highly expressed in a variety of tumors and is associated with high invasion, poor prognosis and poor therapeutic response. However, the expression and role of Sema4D in leukemia remains unclear. The present study investigated the expression of Sema4D in pediatric leukemia and its effects in leukemia cells. The results demonstrated that Sema4D protein was highly expressed in peripheral blood mononuclear cells of patients with pediatric leukemia, and high levels of soluble Sema4D were also observed in the plasma of these patients. Sema4D knockdown induced cell cycle arrest in G0/G1 phase, inhibited proliferation and promoted apoptosis in BALL‑1 cells, while Sema4D overexpression exhibited the opposite effect. In Jurkat cells, Sema4D knockdown inhibited proliferation and promoted apoptosis, while Sema4D overexpression decreased the abundance of the cells in the G0/G1 phase of the cell cycle and promoted proliferation. Sema4D overexpression also increased the migratory capacity of Jurkat cells and the invasive capacity of BALL‑1 cells. The phosphorylation level of PI3K was decreased in both Sema4D knocked‑down Jurkat and BALL‑1 cells, and the phosphorylation level of ERK was decreased in Sema4D knocked‑down BALL‑1 cells. The phosphorylation levels of PI3K, ERK and AKT were elevated in patients with pediatric leukemia, and were correlated to the increased Sema4D expression. Sema4D overexpression was associated with a shorter overall survival in patients with acute myeloid leukemia. Overall, the results of the present study indicated that Sema4D serves an important role in leukemia development by activating PI3K/AKT and ERK signaling, and it may be used as a potential target for the diagnosis and treatment of leukemia.

Keywords: SEMA4D; biomarker; PI3K; ERK; leukemia.

Grant support

The present study was supported by the National Natural Science Foundation of China (grant nos. 81960033 to HJ, 31970868 to QS and 81460028 to MY), the Association Foundation Program of Yunnan Science and Technology Department and Kunming Medical University (grant no. 2019FE001-103 to HJ), the Foundation of the CAMS Initiative for Innovative Medicine (CAMS-I2M) (grant no. 2017-I2M-2-006 to QS), the Foundation of Yunnan Medical Science and Technology (grant no. 2016NS124 to HJ), Yunnan Health Training Project of High Level Talents (grant no. D-2017053 to HJ), Top Young Experts Training Project for the Academy and Technology in Kunming and Yunnan Province to HJ (grant no. 202005AC160066), Postdoctoral Training Program of Yunnan Province (grant no. Ynbh19035 to HJ) and Natural Science Foundation of Yunnan Province (grant no. 2019-1-C-25318000002240 to HJ).