KLK6-dependent gene expression signature as a prognostic marker in head and neck carcinomas

Epithelial-to-mesenchymal transition (EMT) is a dynamic process and critically contributes to treatment resistance, cancer cell dissemination and metastasis. Main objective of this study was to investigate the functional interaction between Kallikrein-related peptidase 6 (KLK6) and aldehyde dehydrogenase 1A (ALDH1A)-related retinoic acid (RA) signaling as recent studies reported their impact on molecular features resembling EMT in several malignancies, including head and neck squamous cell carcinoma (HNSCC). In HNSCC cell lines, we demonstrate that KLK6 is not only a downstream target of ALDH1A-related RA signaling, but also acts as an upstream regulator of ALDH1A3 expression. KLK6 and ALDH1A3 co-expression was confirmed in a mouse xenograft model and two independent HNSCC cohorts (HIPO-HNC and TCGA-HNC). KLK6 and ALDH1A3 co-expressed genes in HNSCC, which are also differentially expression in HNSCC cells with silenced KLK6 expression unraveled several subgroups of HNSCC patients with distinct histopathological and clinical features. In summary, our study highlights a new functional circuit with KLK6 and ALDH1A3 as key nodes and unraveled a gene expression signature, which predicts unfavorable prognosis in human papilloma virus (HPV)-negative HNSCC.

Publikationsverlauf

Publikationsdatum:
23. April 2019 (online)