Keratin proteins including KRT8 and KRT18 serve as important regulators of liver injury, fibrosis, and cancer [25–28]. The prognostic and functional relevance of KRT17 in HCC, however, has not been defined to date. Herein, we analyzed both the TCGA LIHC database and a separate cohort of 44 HCC patients and determined that KRT17 expression levels were significantly higher in HCC tumors relative to normal paracancerous tissues. Elevated KRT17 levels were also identified as a risk factor associated with decrease HCC patient survival.
Through GSEA and functional enrichment analyses, we determined that KRT17 was closely linked to the regulation of many key biological processes including apoptotic signaling, methyl CpG binding, development of the embryonic digestive tract, Notch signaling, and cell cycle pathways. These pathways may be linked to the mechanisms whereby KRT17 governs HCC development and progression.
Dysregulation of the cell cycle and suppression of apoptotic cell death are key hallmarks of oncogenesis, making them prime targets for the treatment of all cancer types [29]. The majority of extant antitumor drugs are anti-mitotic agents, interfering with DNA synthesis and cellular division in a non-targeted manner [30–32]. Herein, we found that the knockdown of KRT17 in HCC cells was associated with G1 phase arrest and a decrease in the frequency of cells in the S phase, while overexpressing KRT17 drove increased rates of apoptotic death. HCC cells. Although there is currently no effective means to inhibit the growth of liver cancer cells, more and more drugs are struggling to target molecular targets for cell growth[33]. Some recent studies proved that growth-inhibiting pathologies (such as E2F and Myc) are effective differentiation inhibitors[34]. We found that knocking down KRT17 was sufficient to suppress the proliferation of HCC cells in vitro and in vivo.
Notch genes encode cell surface receptors that control differentiation and development in myriad species, including humans [35, 36]. Notch signaling can influence apoptosis, proliferation, pluripotent progenitor cell differentiation, and the formation of cell boundaries. Notch gene mutations can result in profound signaling changes and consequent phenotypic effects [35], and keratin family genes are also linked to many key Notch-induced signaling activities [37, 38]. Herein, our GSEA results revealed KRT17 enrichment in the Notch pathway, suggesting that KRT17 may drive dysfunctional HCC cell proliferation, cell cycle progression, and apoptosis at least in part via the Notch signaling pathway.
Tumor immunotherapeutic treatment strategies have revolutionized the standards of care for certain cancer types, and the role of the immune system in the context of cancer progression is increasingly well understood [39, 40]. The composition of the tumor microenvironment has also been studied as a prognostic biomarker [41], and there is prior evidence that immune cell infiltration is linked to liver cancer patient survival [42], consistent with our findings. We additionally found that KRT17 expression levels were associated with the degree of immune cell infiltration in HCC patients such that elevated KRT17 expression was positively correlated with macrophage and activated CD4 + T cell infiltration. Together, these data offer detailed insights into the relationship between KRT17 expression and immune markers in LIHC patients. Future work, however, will be required to understand whether KRT17 is a key factor linked with CD4 + T lymphocyte therapy outcomes.
In summary, our results provide multiple lines of evidence confirming that KRT17 is an important regulator of HCC and a potential prognostic biomarker that can be used to evaluate patients affected by this disease. Specifically, we determine that KRT17 upregulation in HCC tumors is likely to dramatically impact apoptosis, proliferation, and cell cycle progression. In addition, KRT17 may function as a novel immunoregulatory gene in this oncogenic context, underscoring the value of future genomics studies of HCC patient samples.