Abstract
BackgroundTargeting the c-Met signaling pathway has become a therapeutic strategy in multiple types of cancer. We unveiled a novel c-Met regulating mechanism that could be applied as a modality for oral squamous cell carcinoma (OSCC) therapy.MethodsUpregulation of keratin 16 (KRT16) was found by comparing isogenic pairs of low and high invasive human OSCC lines via microarray analysis. OSCC cells with ectopic expression or silencing of KRT16 were used to scrutinize functional roles and associated molecular mechanisms.ResultsWe observed that high KRT16 expression significantly correlated with poorer pathological differentiation, advanced stages, increased lymph nodes metastasis, and decreased survival rate from several Taiwanese OSCC patient cohorts. We further revealed that miR-365-3p could target ETS homologous factor (EHF), a KRT16 transcription factor, to decrease migration, invasion, metastasis and chemoresistance in OSCC cells via inhibition of KRT16. Under confocal microscopic examination, c-Met was found possibly partially associates with KRT16 through β5-integrin. Colocalization of these three proteins may facilitate c-Met and β5-integrin–mediated signaling in OSCC cells. Depletion of KRT16 led to increased protein degradation of β5-integrin and c-Met through a lysosomal pathway leading to inhibition of their downstream Src/STAT3/FAK/ERK signaling in OSCC cells. Knockdown of KRT16 enhanced chemosensitivity of OSCC towards 5-fluorouracil (5-FU). Various combination of c-Met inhibitor (foretinib), protein tyrosine kinase inhibitor (genistein), β5-integrin antibody, and 5-FU markedly augmented cytotoxic effects in OSCC cells as well as tumor killing effects in vitro and in vivo.ConclusionsOur data indicate that targeting a novel miR-365-3p/EHF/KRT16/β5-integrin/c-Met signaling pathway could improve treatment efficacy in OSCC.
Highlights
Targeting the c-Met signaling pathway has become a therapeutic strategy in multiple types of cancer
Overexpression of keratin 16 (KRT16) was found in highly invasive human oral squamous cell carcinoma (OSCC) cell lines and OSCC specimens with clinical significances To derive a highly invasive OSCC sublines, the established human OSCC line OC-3 cells were injected into tail veins of CB17-SCID mice
By analyzing the results derived from gene microarray analysis using Partek software and gene ontology program to compare the invasive phenotypes of the OC-3 vs. OC-3-IV, OC-3 vs. OC-3-IV-M and OC-3-IV vs. OC-3-IV-M (Fig. 1a, Additional file 1: Figure S3a, b and c), we found a series of genes with 4-fold or more differential expression between the OC-3 vs. OC-3-IV-M and OC-3-IV vs. OC-3-IV-M sublines
Summary
Targeting the c-Met signaling pathway has become a therapeutic strategy in multiple types of cancer. We unveiled a novel c-Met regulating mechanism that could be applied as a modality for oral squamous cell carcinoma (OSCC) therapy. Keratins associate with integrins and interact with hemidesmosomes (HDs), which are vital for cell-matrix adhesion and migration [9, 10], and a study reported that keratins were associated with α6β4-integrin through plectin and dystonin and that they played a role in promoting cancer cell properties [11]. Keratins stabilize HDs by regulating integrins and extracellular matrix molecules, suggesting that they might control cancer progression by enhancing integrin signaling function in tumor cells [10, 12]. Keratins play a role in cancer progression, their precise act and signaling pathways in regulating cancer stemness and metastasis, in OSCC, remain unclear
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