KLF4 loss in hepatocellular carcinoma: Improving prognostic prediction and correlating immune infiltrates

Desheng Chen; Qi Zhu; Tiewen Li; Xuhui Fan; Yichao Lou; Yi Zhang; Kejie Huang; Hongcheng Sun

doi:10.3389/fgene.2023.1106952

KLF4 loss in hepatocellular carcinoma: Improving prognostic prediction and correlating immune infiltrates

Front Genet. 2023 Mar 2:14:1106952. doi: 10.3389/fgene.2023.1106952. eCollection 2023.

Authors

Desheng Chen¹, Qi Zhu¹, Tiewen Li², Xuhui Fan³, Yichao Lou¹, Yi Zhang¹, Kejie Huang⁴, Hongcheng Sun¹

Affiliations

¹ Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Institution for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Department of Radiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴ College of Information Science Electronic Engineering, Zhejiang University, Hangzhou, China.

Abstract

Introduction: Although the molecular mechanisms of Krüpple-like factor 4 (KLF4) as a tumor suppressor in HCC tumorigenesis have been thoroughly examined, its clinical application in terms of precise prognostication and its influence on tumor immune microenvironment in patients with HCC require further investigation. Methods: Bioinformatics and immunohistochemistry (IHC) were used to validate KLF4 expressions in a tissue microarray (TMA) containing HCC samples. Using Cox regression models, independent prognostic factors were identified and employed in the development of nomograms. Decision curve analysis (DCA) demonstrated the superiority of the nomograms. GO and KEGG pathway analyses were applied to the functional study of KLF4. The GSVA program explored the link between KLF4 expression and tumor-infiltrating immune cells, and CAMOIP was used to construct KLF4 expression immune scores. Changes in immune-related gene markers were also investigated in relation to KLF4 expression. The association between immune cell infiltration and KLF4 expression was validated by IHC in TMA. Results: HCC was reported to have a notable depletion of KLF4. The absence of KLF4 was associated with advanced clinicopathological characteristics of HCC and predicted a bad prognosis for patients. Nomograms constructed using KLF4 expression, tumor differentiation, and TNM stage provided a more accurate prognostic assessment of HCC patients than TNM stage alone. KLF4 expression was associated with immunological-related functions, infiltration of macrophages, CD8⁺ T cells, and other immune cells, and elevation of immune checkpoints. Higher levels of CD8⁺ T cells and macrophage infiltration are associated with increased KLF4 expression in HCC TMA. Conclusion: KLF4 loss in HCC is a prognostic biomarker that influences the tumor immune microenvironment (TIME).

Keywords: KLF4; biomarker; hepatocellular carcinoma; immune microenvironment; prognosis.

Grants and funding

This study was supported by the Clinical Research Innovation Plan of Shanghai General Hospital (CTCCR-2019C08) and the National Natural Science Foundation of China (81672846).