The Roles of Lif Isoforms in Cancer Progression

Metastasis is the major cause of morbidity and mortality in many cancers, including nasopharyngeal carcinoma. Recently, overexpression of LIF has been correlated with poorer prognosis in several types of cancers. Nevertheless, few studies address how cancer cells dysregulate LIF. Canonical LIF is regarded as a secreted proinflammatory cytokine, exert its effect through LIF receptor. Human LIF exists in at least three isoforms, LIF-D, LIF-M, and LIF-T. Yet, the specific roles of three LIF isoforms in cancer have not been investigated. Here we report that enhanced expression of cytosolic LIF is associated with metastasis of nasopharyngeal carcinoma (NPC). Increased cytosolic LIF-D level endows NPC cells with enhanced invasive ability partly through inducing fibroblastoid changes. In contrast, knocking out LIF-D leads to an opposite consequence. Our data suggest that LIF isoform, LIF-D, may contribute to NPC invasiveness. The proposed studies utilize TALEN or CRISP-knockout in vitro model system, mouse xenograft model, and clinical validations to investigate the roles of LIF isoforms in cancer progression. Specific aims include: 1. determine the specific LIF isoform that accounts for cancer progression and metastasis, 2. determine the spectrum of DNA alterations/mutations across the entire LIF gene in NPC, 3. evaluate the potential benefits of targeting to distinct LIF isoform (e.g., CRISP-mediated gene knockout, LIF antagonist, or a monoclonal antibody) in mouse tumor model. These studies will define roles of LIF isoforms in cancer invasiveness and metastasis. The identification of LIF genetic mutations may potentially be used as prediction biomarkers for prognosis.

Project ID:PC10507-0634
External Project ID:MOST105-2314-B182-032