口腔鱗狀上皮細胞癌（OSCC）具高度復發與轉移傾向，與癌症幹細胞的特性 密切相關。具癌症幹細胞特性（cancer stemness）之癌細胞在腫瘤中具備自我更新 能力與治療抗性，被視為腫瘤進展與復發的重要因子。 儘管近年來研究指出 cancer stemness 與腫瘤微環境之間可能存在交互作用 ， 但在 OSCC 中調控 cancer stemness 的分子機制仍有待釐清。本研究旨在探討白血病抑制因子受體（leukemia inhibitory factor receptor, LIFR）於 OSCC 細胞中調控癌症 cancer stemness 與侵犯性之角色。 結果發現，相較於鄰近正常上皮細胞，自發性永生化之 OSCC 細胞株（TWOC） 之 LIFR 表現顯著上升 。定序資料的分析顯示，該 OSCC 細胞株具備明顯的 cancer stemness 與侵犯性表現。臨床檢體的免疫組織化學染色進一步發現，LIFR 於腫瘤 組織中，特別是在腫瘤邊緣之表現顯著增強 ，顯示其可能與癌細胞之侵犯行為具有 關聯。功能性實驗顯示，抑制 LIFR 表現會降低 TERT 蛋白表現，並透過 QTRAP 實驗證實 LIFR 對 TERT 活性具有調控作用。此外 ，過度表現 LIFR 的 OSCC 細 胞呈現紡錘狀外型並具有較高的增殖能力，反之，降低 LIFR 表現則使細胞外型趨 於扁平，呈現分化狀態。血管內皮細胞（HUVEC）層取代實驗結果亦顯示，LIFR 表現提升之 OSCC 細胞具較強的血管層破壞能力，而抑制 LIFR 則明顯削弱此能 力。綜合以上結果，本研究指出 LIFR 有助於維持 OSCC 細胞之 cancer stemness 並促進其侵犯能力。;Oral squamous cell carcinoma (OSCC) is characterized by a high incidence of locoregional recurrence and metastasis, which are closely associated with the presence of cancer stem cells. Cancer cells with stem-like properties possess self-renewal capacity and therapy resistance, making them key drivers of tumor progression and relapse. Although recent studies have suggested a possible interaction between stemness and the tumor microenvironment, the molecular mechanisms regulating stemness in OSCC remain largely to be explored. In this study, we investigated the role of leukemia inhibitory factor receptor (LIFR) in regulating cancer stemness and invasiveness in OSCC cells. Elevated LIFR expression was found in a spontaneously immortalized OSCC cell strain (TWOC), compared to the adjacent normal basal epithelial cells. NGS analysis revealed that the established OSCC strain exhibited characteristics of cancer stemness and invasiveness. Immunohistochemical analysis on clinical samples revealed enhanced LIFR expression in tumor tissues, especially at the invasive fronts of tumor nests, suggesting potential correlation of LIFR and cancer invasiveness. Functional assays further demonstrated that knocking down LIFR reduced the levels of TERT. QTRAP assays further confirmed the role of LIFR in regulating TERT activity. Additionally, OSCC cells expressing higher levels of LIFR exhibited a spindle-like morphology and an increased cell proliferation, while knocking down LIFR resulted in a flattened, differentiated appearance. Moreover, results of endothelial (HUVEC) layer replacement assay proved that LIFR overexpression enhanced disruptive ability of OSCC cells towards HUVEC layers, while LIFR-knockdown OSCC cells showed limited damaging ability towards HUVEC layers. Together, these findings suggest that LIFR contributes to maintaining stem-like properties and promoting cancer invasiveness in OSCC.
