Proteome expression profiling of red blood cells during the tumorigenesis of hepatocellular carcinoma

PLoS One. 2022 Nov 8;17(11):e0276904. doi: 10.1371/journal.pone.0276904. eCollection 2022.

Abstract

The early diagnosis of hepatocellular carcinoma (HCC) has not been clinically elucidated, leading to an increased mortality rate in patients with HCC. HCC is a systemic disease related to disorders of blood homeostasis, and the association between red blood cells (RBCs) and HCC tumorigenesis remains elusive. We performed data-independent acquisition proteomic analyses of 72 clinical RBC samples, including HCC (n = 30), liver cirrhosis (LC, n = 17), and healthy controls (n = 25), and characterized the clinical relevance of RBCs and tumorigenesis in HCC. We observed dynamic changes in RBCs during HCC tumorigenesis, and our findings indicate that, based on the protein expression profiles of RBCs, LC is a developmental stage closely approaching HCC. The expression of hemoglobin (HbA and HbF) in peripheral blood dynamically changed during HCC tumorigenesis, suggesting that immature erythroid cells exist in peripheral blood of HCC patients and that erythropoiesis is influenced by the onset of LC. We also identified the disrupted autophagy pathway in RBCs at the onset of LC, which persisted during HCC tumorigenesis. The oxytocin and GnRH pathways were disrupted and first identified during the development of LC into HCC. Significantly differentially expressed SMIM1, ANXA7, HBA1, and HBE1 during tumorigenesis were verified as promising biomarkers for the early diagnosis of HCC using parallel reaction monitoring technology. This study may enhance the understanding of HCC tumorigenesis from a different point of view and aid the early diagnosis of HCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / metabolism
  • Carcinoma, Hepatocellular* / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Erythrocytes / metabolism
  • Humans
  • Liver Cirrhosis / diagnosis
  • Liver Neoplasms* / metabolism
  • Membrane Proteins
  • Proteome
  • Proteomics

Substances

  • Proteome
  • Biomarkers, Tumor
  • SMIM1 protein, human
  • Membrane Proteins

Grants and funding

This study was supported by the National Natural Science Foundation of China (Grant No. 32071117, 81870097). The funder had no role in the study design, data collection and analysis, decision to publish, or manuscript preparation. Shufang Wang and Zhaojun Zhang received specific funding for this study (Grant No. 32071117 to Shufang Wang and Grant No. 81870097 to Zhaojun Zhang).