Cancer Biology (癌症生物學), Oncogenes (促癌基因), Tumor Suppressor Genes (抑癌基因), Oral squamous cell carcinoma (口腔癌), Lymphatic metastasis (淋巴轉移), EMT (epithelial mesenchymal transition), Mouse model of oral cancers(口腔癌小鼠模式), Cancer stemness(癌症幹細胞特性), Signaling pathways (訊息路徑), Migration(移動), Radiation sensitivity (放射敏感性), Tumor-associated microenvironment (腫瘤微環境)
口腔癌(oral squamous cell carcinoma, OSCC)中 ，發生淋巴結轉移(lymph node metastasis)的患者，其癒後明顯比無轉移的患者差。 他們的5年總生存率(overall survival， OS)約為45％，而沒有淋巴結轉移的患者則可高達80％。由此可見， 若能對於OSCC病人進行淋巴轉移的評估，不僅有利於了解患者癒後情況，更能給予患者更適切的治療方式。釐清口腔癌淋巴轉移生理機轉，對於早期診斷和治療會有莫大幫助。 為了解口腔癌淋巴轉移，實驗室利用免疫缺陷鼠(immune-deficient mice)進行體內篩選(in vivo selection)，已建立了穩定的高淋巴轉移能力的口腔癌細胞分株 (Yen et al. Oncotarget, 2015)。 另外，實驗室利用經4NQO及Acrecoline處理正常免疫小鼠產生口腔癌，取其腫瘤部份經培養後，成功建立同源小鼠口腔癌細胞株 (Chen et al. Cancers, 2019)。藉由這些不同特性的口腔癌細胞株，探討以下口腔癌形成與淋巴轉移 (tumorigenesis and lymph node metastasis of OSCC)相關重要議題，包括了治療標的及生物標記研發：
- Yen et al. Molecular Cancer, 2014
- Yen et al. Oncotarget, 2015
- Chen et al. Oncogene, 2019
- Chen et al. Scientific Reports, 2021
(2) 口腔癌細胞與腫瘤相關微環境(例如：免疫細胞(immune cells)，Cancer-associated fibroblast (CAFs)和淋巴內皮細胞(lymphatic endothelial cells, LECs)的交互作用。
(3) 尋找與口腔癌腫瘤生長 (tumor growth)和淋巴轉移(lymph node metastasis)相關生物標記 (biomarkers)及治療標的(therapeutic targets)。
(4) 研究口腔癌細胞的外泌體(exosomes)和分泌因子(secreted factors)的成分及其作用。
(5) 研究放射治療(radiation therapy)對口腔癌細胞的分子影響。
RESEARCH ACTIVITIES & ACCOMPLISHMENT
(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).
(8) Insulin-like growth factor binding protein 3 promotes radiosensitivity of oral squamous cell carcinoma cells via positive feedback on NF-κB/IL-6/ROS signaling. (Wang at al. JECCR, 2021)
Illustration of the role of IGFBP3 in enhancement of radiosensitivity in OSCC cells via the NF-kB/IL-6/ROS signaling axis. Ectopic IGFBP3 expression enhances NF-kB activity, induces expression of inflammatory cytokines, such as IL-1b, IL-8 and IL-6. Upon IR, ROS initiates the axis of NF-kB/IL-6/ROS and forms positive feedback. The ROS is highly amplified in IGFBP3-expresing cells upon IR and lead to cell apoptosis via mitochondria-dependent cell death.