Cancer Biology, Oncogenes, Tumor Suppressor Genes, Oral squamous cell carcinoma, Lymphatic metastasis, EMT (epithelial mesenchymal transition), Mouse model of oral cancers, Cancer stemness, Signaling pathways, Migration, Radiation resistance
Our research interest is focusing on cancer metastasis, a major cause of poor prognosis in oral squamous cell carcinoma (OSCC). Recently, our Lab has established an orthotopic model for lymph node metastasis of OSCC cells in immune-deficient mice and successfully generated OSCC sublines with high potential of lymphatic metastasis (Yen et al. Oncotarget, 2015). Also, we successfully established a novel mouse OSCC cell line to investigate the interplay of OSCC cells and immune system (Chen, et al. Cancers, 2019). Based on these unique cell lines, our studies focus on:
(1) Investigating the mechanisms of lymphatic metastasis.
- Yen et al. Molecular Cancer, 2014
- Yen et al. Oncotarget, 2015
- Chen et al. Oncogene, 2019
- Chen et al. Scientific Reports, 2021
(2) Investigating the Interaction between OSCC cells and tumor associated microenvironment, such as immune cells, cancer-associated fibroblasts (CAFs) and lymphatic endothelial cells (LECs).
(3) Investigating the potential biomarkers and therapeutic targets for tumor growth and lymphatic metastasis of OSCC.
(4) Investigating the effects of OSCC cell-derived exosomes and secreted factors on tumor growth and lymph node metastasis of OSCC.
(5) Investigating pre-metastatic niche in lymph nodes.
(6) Investigating the sensitizers for radiation in OSCC therapeutics.
(7) Investigating the mechanisms of radiation-induced metastasis.
RESEARCH ACTIVITIES & ACCOMPLISHMENT
Oral squamous cell carcinoma (OSCC) patients with lymph node metastasis have a notably worse prognosis than that of patients without metastasis; they have a 5-year overall survival rate of approximately 45% compared with 80% for those without lymph node metastasis. An accurate assessment of the lymph node status in OSCC not only helps determine the prognosis of patients but also aids in the selection of appropriate treatments. Therefore, understanding the pathophysiology of lymph node metastasis in OSCC is important for early diagnosis and treatment. To address this, we have some important findings, including:
(1) Reciprocal regulation of microRNA-99a and insulin-like growth factor I receptor signaling in oral squamous cell carcinoma cells. (Yen et al. Molecular Cancer, 2014)
|We found that ectopic miR-99a expression downregulates insulin-like growth factor 1 receptor (IGF1R) protein and that the expression of miR-99a correlates negatively with IGF1R protein in OSCC cells. This reciprocal regulation of miR-99a and IGF1R signaling augmented the activation of the IGF1R signaling pathway in response to IGF1 stimulation and accelerated its inactivation following the removal of stimulation.|
(2) Insulin-like growth factor-independent insulin-like growth factor binding protein 3 (IGFBP3) promotes cell migration and lymph node metastasis of oral squamous cell carcinoma cells by requirement of integrin β1. (Yen et al. Oncotarget, 2015)
|We found that ectopic expression of IGFBP3 with an IGF-binding defect sustained the IGFBP3-enhanced biological functions and IGFBP3 regulates metastasis-related functions of OSCC cells through an IGF-independent mechanism. Furthermore, exogenous IGFBP3 was sufficient to induce cell motility and extracellular signal-regulated kinase (ERK) activation. The silencing of integrin β1 was able to impair exogenous IGFBP3-mediated migration and ERK phosphorylation, suggesting a critical role of integrin β1 in IGFBP3-enchanced functions.|
(3) Tumour cell-derived WNT5B modulates in vitro lymphangiogenesis via induction of partial endothelial-mesenchymal transition (EndoMT) of lymphatic endothelial cells. (Wang, et al. Oncogene, 2017)
|Tumor cell-derived WNT5B binds to the receptor on LECs and activated the signaling pathways of WNT/β-catenin and noncanonical WNT signaling pathways through β-catenin activation and JNK phosphorylation. Subsequently, the increased expression of Snail and Slug contributes to a partial endoMT and in vitro lymphangiogenesis.|
(4) Laminin γ2-enriched extracellular vesicles of oral squamous cell carcinoma cells enhance in vitro lymphangiogenesis via integrin α3-dependent uptake by lymphatic endothelial cells. (Wang et al. IJC, 2019)
Based on the proteomic approach, laminin-332 was highly expressed in extracellular vesicles (EVs) from oral squamous cell carcinoma cells with lymphatic metastasis. Clinically, Laminin-332-bearing EV can serve as a diagnostic biomarker for lymphatic metastasis. Additionally, the genetic approach substantiated the in vitro and in vivo interplay of Laminin-332-bearing EV and integrin α3 in uptake of lymphatic endothelial cells, indicating that the blockage of EV uptake emerges as a therapeutic strategy for tumor lymphangiogenesis.
(5) Interferon-stimulated gene 15 (ISG15) modulates cell migration by interacting with Rac1 and contributes to lymph node metastasis of oral squamous cell carcinoma cells. (Chen et al. Oncogene, 2019)
|A novel function of intracellular free ISG15 is to mediate cell migration through regulation of Rac1 activity by binding to Rac1-GDP and facilitate Rac1-GDP/GTP exchange. Rho-GDI sequesters inactive GDP-bound Rac1 in cytoplasm. Rac1-GDP relocates to the plasma membrane and interact with ISG15 when released from Rho-GDI. On the membrane, GEFs mediates Rac1 activity by promoting its GTP-loading and Rho-GTPase activity. GAPs in turn inactivate Rac1 by promoting GTP hydrolysis to GDP.|
(6) ERK activation modulates cancer stemness and motility of a novel mouse oral squamous cell carcinoma cell line. (Chen at al. Cancers, 2019)
NHRI-HN1 is highly tumorigenic in vivo by orthotopic injection into immune-competent hosts. Stimulation of host immunity dramatically affected the tumorigenic process, illustrating the model’s advantage for studying immune escape of OSCC. NHRI-HN1 cells, characterized by an epithelial mesenchymal transition (EMT) also demonstrated enhanced migration and invasion. NHRI-HN1’s enhanced functions were suppressed by mitogen-activated protein kinase (MAPK) kinase inhibitors, suggesting an essential role for sustained extracellular signal-regulated kinase (ERK) phosphorylation in target therapy of OSCC.
(7) Ephrin A4-ephrin receptor A10 signaling promotes cell migration and spheroid formation by upregulating NANOG expression in oral squamous cell carcinoma cellsE. (Chen et al. Scientific Reports, 2021)
The role of ephrin A4 (EFNA4)-ephrin receptor A10 (EPHA10) forward signaling in promoting OSCC tumorigenesis and metastasis. EFNA4 from adjacent tumor cells or stromal cells binds to EPHA10 on OSCC cells and induces extracellular signal-regulated kinase (ERK) activation. ERK activation drives progressive effects, including cell migration and spheroid formation, and up-regulation of NANOG expression. NANOG is required for EFNA4-induced cell migration and sphere formation (indicated as dark blue dashed arrows).