Investigation of the Mechanisms of Ifit2 Depletion-Induced Cancer Cachexia in Head and Neck Cancer

IFIT2 (interferon-induced protein with tetratricopeptide repeat 2) is a member of the IFIT1 family of interferon-stimulated genes (ISGs). Our series of studies have confirmed that IFIT2 depletion enhances atypical protein kinase C (aPKC) activation, TNF-α upregulation, epithelial-mesenchymal transition (EMT), angiogenesis, invasion, and metastasis in head and neck cancer (HNC) cells. Clinically, patients with HNC with less IFIT2 expression have a higher distant metastatic rate and a worse prognosis. Recent experimental results demonstrated that human HNC CAL27 cells expressing sh-IFIT2 (shIFIT2) injected intravenously into NOD/SCID mice triggered severe cachexia symptoms such as anorexia, weight loss, and muscle atrophy. Under the same experimental conditions, the injection of CAL27 cells expressing sh-control (shCTRL) into mice had no significant change in body weight, showing that IFIT2 deletion can induce cachexia in HNC. In addition, the same numbers of sh-IFIT2 cells were implanted subcutaneously in the backs of NOD/SCID mice had no significant changes in weight loss, suggesting that the IFIT2 depletion-induced cachexia is related to metastasis microenvironment. The HCYTMAG-60K-PX41 and MCYTOMAG-70K-PX32 technologies were used to compare the cytokine levels in the serum of the two shIFIT2 hosts and healthy hosts. The results showed that the tumor-releasing factors IL6 and CCL2 increased significantly in the serum of cachectic hosts; consequently, the host response cytokine IL6 increased significantly in the serum of cachectic hosts. Experiments using C2C12 myotubes also confirmed that IL6 and CCL2 are involved in FITT2 depletion-induced muscle atrophy. We are the first study to confirm that the deletion of the IFIT2 protein induces cachexia in HNC. The development of cachexia varies in different cancers. Studying the detailed mechanism and clinical significance of IFIT2 depletion-induced HNC cachexia can confirm the involvement of IFIT2 on the HNC progression, especially at metastasis and cachexia stage. Therefore, this project will explore (1) the mechanism regarding muscle atrophy in sh-IFIT2 cachectic hosts; (2) the effect of IL6 and CCL2 in the IFIT2 depletion-induced cachexia; (3) the regulatory role of IFIT2 on IL6 and CCL2 expression; (4) the involvement of myeloid-derived suppressor cells (MDSC) expansion in IFIT2 depletion-induced cancer cachexia; (5) correlation of IFIT2, IL6, and CCL2 expression and its clinical significance in HNC patients. The results of this project can be applied to the prevention, diagnosis and treatment of HNC cachexia.

Project ID:PC10908-0022
External Project ID:MOST109-2320-B182-044