The novel function of keratin 14 (KRT14) in regulating cancer stem cell properties in lung adenocarcinoma

Lung cancer remains the leading cause of cancer deaths worldwide. Among all classification subtypes, lung adenocarcinoma (LUAD) accounts for the largest proportion of all cases of lung cancer. Although the expanding development of novel targeted therapies has been improving the overall survival of lung cancer patients, recurrence and therapeutic resistance remains as the major reasons of treatment failure. Cancer stem cells (CSCs) have been revealed to be one of the major drivers for tumor recurrence and therapeutic resistance. Understanding the molecular pathways in regulating CSCs may provide insights on designing novel drug combinations in targeting the disease. Various studies showed that there is a contrasting expression of keratins in stem and differentiated cells, implying the functional importance of keratins in maintaining stem cell characteristics. Keratin 14 (KRT14) is a keratin isoform shown to be enriched in breast and bladder CSCs. In LUAD, KRT14 has been reported to be a key player in tumor invasion, yet its role in regulating LUAD CSCs remains largely unknown. In this study, we aim to delineate the clinical significance and the functional role of KRT14in LUAD. From The Cancer Genome Atlas (TCGA) data, the mRNA expression of KRT14 was found to be higher in LUAD tumor when compared with paired normal tissues (p=0.0057).This data was also confirmed in protein level with our in-house cohort, in which LUAD tumor showed an upregulation of KRT14 protein expression. TCGA data also revealed that patients with high KRT14 mRNA expression have a poorer disease-free survival (p=0.0147) and overall survival (p=0.0043). By qPCR and western blot analyses, we found that the expression of KRT14 is upregulated in our established enriched lung CSC population. Using lenti-viral based knockdown approach, KRT14 was found to regulate the traits of CSCs, including tumorigenicity, self-renewal, drug resistance and the expression of lung CSC markers. Interestingly, KRT14 was found to be upregulated in the erlotinib-resistant LUAD cells, and the abrogation of KRT14 expression re-sensitized these cells to erlotinib treatment. The genetic profiles of KRT14 knockdown and control cells will be compared in the future to identify the potential downstream targets of KRT14 in regulating lung CSCs. In summary, our study highlights the crucial role of KRT14 in maintaining lung CSCs and may provide a novel therapeutic target for the disease. Citation Format: Isabella Kit-Nam Chin, Goretti Hoi-Yan Cheung, Hazel Yuk-Yan Kwok, Victor Wan-San Ma, Eunice Yuen-Ting Lau, William Chi-Shing Cho. The novel function of keratin 14 (KRT14) in regulating cancer stem cell properties in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3067.