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

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.

Red blood cell-tumour cell interactions promote tumour cell progression

“…Additionally, Helwa et al proposed that tumour cells may interact with RBCs, potentially through galectin-4, which although primarily expressed in gastrointestinal epithelial cells, has implications in various cancers 8 . Furthermore, we have recently observed that the presence of RBCs in CTCs short-term cultures is associated with poorer patient outcomes 14 and we have also demonstrated that the protein profiles of RBCs in cancer patients are altered compared to cancer-free donors 15,16 .…”

Haemoglobin, albumin, lymphocyte, and platelet (HALP) score is a useful predictor of prognosis after hepatectomy for hepatocellular carcinoma: a retrospective, propensity score matching cohort study

“…However, Mcfadzean et al reported that patients with HCC have lower haemoglobin levels than healthy controls [13]. Wang et al revealed that decreased haemoglobin levels are associated with HCC tumourigenesis [14]. Furthermore, Boogaerts et al reported that anaemia induces tumour hypoxia, facilitates tumour-associated changes within neoplastic cells, and promotes tumour survival and malignant progression [15].…”

RBC-GEM: a Knowledge Base for Systems Biology of Human Red Blood Cell Metabolism

“…We also included a high-confidence canonical erythrocyte proteome defined by reconciling proteomic data through supervised machine learning [86]. There is increasing interest in using RBCs within the context of clinical proteomics [91] and transfusion medicine [29]; therefore, we included several studies that explore alterations in the RBC proteome due to various pathological disease states [75,80,83,85,87,88] and refrigerated storage under blood bank conditions [26,84,85], increasing the utility of RBC-GEM for biomarker discovery [43]. Because several proteomic datasets contained outdated and alternate accessions [18,19,[70][71][72][73][74]76], the unavoidable consequence of routine database updates and previous database deprecations [92], we consolidated all identifiers into a list and utilized UniProtKB mapping service to update all protein identifiers to current UniProtKB accessions, pruning obsolete and unreviewed proteins from the list.…”