LAUSR

Hepatocellular carcinoma (HCC) ranks as the fifth most common cancer and the second leading cause of cancer-related mortality worldwide. The overall prognosis of HCC patients is very poor because it is susceptible to recurrence and metastasis. According to the cancer stem cell (CSC) model, there is a small subset of cancer cells within the tumor bulk that is responsible for tumor relapse and metastasis. CSCs represent cells that can self-renew, initiate tumors, and keep resistant to anti-cancer treatment. However, the fate and signatures of CSCs in HCC remain elusive. Our previous in vitro hepatocyte differentiation model successfully mimicked the liver developmental process from the stage of embryonic stem cells, endoderm, liver progenitor cells, and premature hepatocytes, together with one pair of nontumor and tumor tissue from an HCC patient. We found that the expression of keratin 17 (KRT17) reached its peak at the liver progenitor stage and was down-regulated along with liver development, which shared the same expression pattern with keratin 19 (CK19), a well-known HCC stemness-associated gene. Single-cell RNA sequencing in 9 HCC clinical samples from the GEO dataset revealed that KRT17 was expressed in less than 1% of tumor cells. Moreover, KRT17 shared similar expression patterns among hepatocytes, non-stem like HCC and stem like HCC subpopulations with a panel of hepatic stem cell markers and showed reverse trends with a list of hepatic markers. Clinically, KRT17 was highly expressed in cancer tissues compared to normal counterparts and positively correlated with poor overall survival. Functional assays indicated that KRT17 could considerably facilitate the self-renewal, growth, and metastasis properties of HCC both in vitro and in vivo. Also, KRT17 endowed HCC cells with enhanced resistance to sorafenib treatment. Moreover, the expressions of the CSC marker (CD133) and oncofetal drivers (NANOG and KLF4) were significantly upregulated upon KRT17 overexpression. Bioinformatic analysis using gene expression profiles of patients from the TCGA database revealed that development- and differentiation-related biological processes were dramatically enriched in KRT17-high patients. The underlying molecular mechanism of how KRT17 augments HCC stemness still needs further study. Overall, our study uncovered a new connection between KRT17 and HCC stemness and progression. KRT17 might be a novel marker of CSC and a prognostic biomarker for the treatment of HCC patients. Citation Format: Xiaona Fang, Shan Liu, Liuxian Ban, Jiao Huang, Jie Luo, Lanqi Gong, Baifeng Zhang, Beilei Liu, Jinlin Huang, Yuma Yang, Ching Ngar Wong, Qian Yan, Xin-Yuan Guan. Identification and characterization of the role of KRT17 in the stemness regulation of hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2441.