Lysyl oxidase‐like 2 promotes stemness and enhances antitumor effects of gefitinib in head and neck cancer via IFIT1 and IFIT3

Abstract

Lysyl oxidase‐like 2 (LOXL2) is a matrix‐remodeling enzyme that has recently been identified as an important regulator of tumor progression and metastasis. This study discovered that LOXL2 expression in oral squamous cell carcinoma (OSCC) tissues was significantly associated with tumor clinical stage, lymph node metastasis and patients' overall survival time. LOXL2‐overexpressing human buccal SCC TW2.6 (TW2.6/LOXL2) and hypopharyngeal SCC FaDu (FaDu/LOXL2) cells exhibited enhanced migration, invasion, epithelial–mesenchymal transition (EMT), and cancer stem cell (CSC) phenotypes, independently of its enzymatic activity. Moreover, TW2.6/LOXL2 significantly increased tumor‐initiating frequency in SCID mice. We further demonstrated that LOXL2 increased the levels of interferon‐induced protein with tetratricopeptide repeats 1 (IFIT1) and IFIT3 in TW2.6/LOXL2 and FaDu/LOXL2 cells. We also identified IFIT1 and IFIT3 as key downstream components of LOXL2 action in migration, invasion, EMT, and CSC phenotypes in TW2.6 and FaDu cells. Furthermore, a significant positive correlation between LOXL2 expression and IFIT1 and IFIT3 overexpression in human OSCC tissues was observed. In addition, TW2.6/LOXL2 and FaDu/LOXL2 cells were 3.3‐ to 3.6‐fold more susceptible to the epidermal growth factor receptor (EGFR) inhibitor gefitinib than were their respective control cells. The antitumor effect of gefitinib on orthotopic TW2.6/LOXL2 xenograft tumor was fourfold higher than that on controls. Our results indicate that LOXL2 expression is a strong prognostic factor for OSCC and may be used as a marker to identify patients most likely to respond to EGFR‐targeted therapy.

The expression of immune co-stimulators as a prognostic predictor of head and neck squamous cell carcinomas and oral squamous cell carcinomas

“… 29 The inoculation of MTCQ1 isografts into the buccal space of C57BL/6J mice (National Laboratory Animal Center, Taipei, Taiwan) was performed. 30 This approach, along with the subsequent resection, processing, and RNA-Seq analysis of the grafts and the adjacent buccal mucosa, insighted the changes of gene transcription in murine syngeneic OSCC tumors. The expression matrix of genes shown as TPM values was then subjected to analysis.…”

The high expression of immune checkpoint co-stimulators predicts a favorable prognosis in head and neck carcinomas

“…was performed [30]. After sacrificing animals, the grafts and the adjacent buccal mucosa were resected, processed, and subjected to RNA-Seq.…”