口腔鱗狀癌細胞的抗藥性經常導致腫瘤的復發和轉移，而這仍然是一個未解決的挑戰。越來越多的報導指出，癌症幹細胞的存在是抗藥性、腫瘤復發和轉移的關鍵因素。因此，找出調節癌症幹細胞的機制和開發其抑製劑將有助於改善口腔鱗狀癌細胞的治療。在這項研究中，觀察到在高侵襲性的口腔鱗狀癌細胞和晚期腫瘤組織中KRT17的表達顯著升高，並且較高的KRT17表達與較差的存活率相關。減少口腔鱗狀癌細胞中的KRT17基因表達會減弱它們幹細胞的特性，包括顯著降低的球體形成能力以及幹細胞和上皮細胞間質轉化標記物的表達。我們確定了一個由KRT17新型的信號傳遞過程，就是KRT17與plectin結合導致integrin β4/α6的活化，FAK、Src和ERK的磷酸化增加，以及β-catenin的穩定化和進入細胞核。這信號傳遞反應與增強口腔鱗狀癌細胞的幹細胞特性、以及CD44和EGFR的表達升高息息相關。我們證明了KRT17是miRNA-485-5p的直接靶標。增強miRNA-485-5p的表達能夠抑制口腔鱗狀癌細胞球體的形成並增加癌細胞對cisplatin和carboplatin敏感性，上述這些抑制現象可透過KRT17 的高表達來挽救。Dasatinib可以抑制KRT17引發的Src活化也可以造成口腔鱗狀癌細胞對藥物更敏感。在人類口腔鱗狀癌細胞異種移植小鼠模型中，減少癌細胞中KRT17的表達顯著抑制了腫瘤生長，加上cisplatin的聯合治療有更明顯的抑制腫瘤作用。如所預期，在此減少KRT17表達的小鼠模型實驗中也觀察到integrin β4、active β-catenin、CD44和EGFR的表現量顯著降低。總結來說，我們的研究揭露了一種新型的miRNA-485-5p/KRT17/integrin/FAK/Src/ERK/β-catenin訊息傳導途徑，具有調控口腔鱗狀癌細胞的幹細胞特性和對化療藥物抗藥性的功能。我們這項研究為抑制口腔鱗狀癌細胞提供了一種新的治療策略。

The development of drug resistance in oral squamous cell carcinoma (OSCC) leading to recurrence and metastasis after initial treatment remains an unresolved challenge. Presence of cancer stem cells (CSCs) has been increasingly reported to be a critical contributing factor in drug resistance, tumor recurrence and metastasis. Thus, unveiling the mechanisms regulating CSCs, as well as useful targets for developing CSCs inhibitors will be instrumental for improving OSCC therapy. In this study, we observed significantly elevated expression of KRT17 in highly invasive OSCC cell lines and advanced tumor specimens and high KRT17 expression was correlated with poor overall survival. KRT17 gene silencing in OSCC cells attenuated their stemness properties including markedly reduced sphere-forming ability and expression of stemness and EMT markers. We identified a novel signaling cascade orchestrated by KRT17 where its association with plectin resulted in activation of integrin β4/α6, increased phosphorylation of FAK, Src and ERK, as well as stabilization and nuclear translocation of β-catenin. The activation of this signaling cascade was correlated with enhanced OSCC cancer stemness and elevated expression of CD44 and epidermal growth factor receptor (EGFR). We demonstrated KRT17 to be a direct target of miRNA-485-5p. Ectopic expression of miRNA-485-5p inhibited OSCC sphere formation and caused sensitization of cancer cells towards cisplatin and carboplatin, which could be significantly rescued by KRT17 overexpression. Dasatinib treatment inhibited KRT17-mediated Src activation and increased OSCC chemo drug sensitivity. In OSCC xenograft mouse model, KRT17 knockdown significantly inhibited tumor growth, and combinatorial treatment with cisplatin elicited a greater tumor inhibitory effect. Consistently, markedly reduced levels of integrin β4, active β-catenin, CD44 and EGFR were observed in the tumors induced by the KRT17 knockdown OSCC cells. Taken together, we have unveiled a novel miRNA-485-5p/KRT17/integrin/FAK /Src/ERK/β-catenin signaling pathway that is capable of modulating OSCC cancer stemness and drug resistance to the common first-line chemotherapeutics. This provides a potential new therapeutic strategy to inhibit OSCC stem cells and counteract chemoresistance.

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