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Label-free proteomic analysis of the HCC secretome and compared the protein profiles of human PLC liver cancer cells with that of human THLE3 hepatocytes secreted in conditioned medium

ABSTRACT: To identify potential factors related to the development and progression of HCC, we employed label-free proteomic analysis of the HCC secretome and compared the protein profiles of human PLC liver cancer cells with that of human THLE3 hepatocytes secreted in conditioned medium.

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ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hepatocyte

SUBMITTER: Ting Wang

LAB HEAD: Huafeng Zhang

PROVIDER: PXD033437 | Pride | 2023-02-15

REPOSITORIES: Pride

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Project description:Kidney stones (KS) are very common, excruciating, and are associated with tremendous healthcare cost, chronic kidney disease (CKD), and end stage renal disease (ESRD). Most KS are composed of calcium oxalate and very small increases in urine oxalate concentration increase the risk for stone formation. Besides its critical role in the pathogenesis of KS, emerging data suggest that disturbed oxalate homeostasis (hyperoxaluria and/or hyperoxalemia) contributes to CKD progression, CKD - and ESRD-associated cardiovascular diseases, progression of cyst growth in autosomal dominant polycystic kidney disease (ADPKD), and delayed graft function & poor renal allograft survival. This emphasizes the urgent need for plasma and urinary oxalate lowering therapies, and enhancing the bowel’s ability to secrete oxalate may effectively do so. We previously identified Oxalobacter formigenes (O. formigenes)-derived factors secreted in its culture conditioned medium (CM) which stimulated oxalate transport by human intestinal Caco2-BBE (C2) cells and reduced urinary oxalate excretion in hyperoxaluric mice by enhancing colonic oxalate secretion. Given their remarkable therapeutic potential, we now identified several proteins belonging to Sel1-like family as the major O. formigenes-derived secreted factors, and we determined the crystal structures for six proteins to better understand their function. Importantly, Sel1-14-derived small peptides P8 & P9 were identified as the major factors, with P8+9 closely recapitulate the CM’s effects, including acting through the oxalate transporters SLC26A2 & SLC26A6 and PKA activation. P8+9 also stimulate oxalate transport by human ileal and colonic organoids, confirming that these peptides work in human tissues. Collectively, the identification of these small peptides provide a great opportunity for developing a peptide-based novel therapeutic for hyperoxalemia, hyperoxaluria, and related disorders, impacting the outcomes of patients suffering from KS, primary hyperoxaluria, CKD, ADPKD, ESRD, and renal transplant recipients.

Project description:Abstract Background and aims. Hepatocellular carcinoma (HCC) shows limited response to checkpoint inhibitors, leaving opportunity for antigen-based immunotherapy and improved disease monitoring. This study evaluates plasma-derived soluble HLA-I (sHLA-I) peptidome as a minimally invasive source of tumor antigens by comparing them to tumor and adjacent tissue HLA ligands to assess its value for personalized treatment and diagnostics in HCC. Methods. Plasma-derived soluble HLA-I complexes and membranous HLA-I ligands from paired tumor and adjacent liver tissues of HCC and non-HCC control patients were isolated using pan-HLA-I immunoprecipitation and analyzed by LC-MS/MS. Peptide identification and patient-specific HLA binding predictions were complemented by annotation of tumor-associated antigens (TAAs) to compare ligand repertoires across HLA sources. Results The plasma soluble HLA-I (sHLA-I) peptidome from HCC and non-HCC patients was successfully characterized, with 1,553 to 9,421 unique peptides identified per sample after contaminant filtering. Peptides were enriched for canonical 8–11-mer lengths, with most predicted to bind patient-specific HLA-I alleles. Among 3,907 source proteins delivering peptides to the HCC sHLA-I peptidome, 815 were unique to HCC patients, and protein interaction analysis revealed significantly increased network connectivity centered around tumor-associated proteins. Comparison with membranous HLA-I (mHLA-I) peptidomes from tumor and adjacent tissues yielded 20 peptides from 17 tumor-associated antigens (TAAs) that were shared between sHLA-I and mHLA-I. Nine of these were only identified from HCC plasma and not from non-HCC controls, five overlapped with tumor mHLA-I. Conclusions. This pilot study demonstrates that the plasma-derived soluble HLA-I immunopeptidome in HCC patients contains peptides derived from TAAs, at least partially reflective of those presented on tumor tissue. These findings support the potential of sHLA-I profiling as a minimally invasive strategy for identifying actionable targets and tumor-specific signatures in HCC. Future improvements in analytical sensitivity and throughput, and validation in larger cohorts are now needed to establish its clinical utility.

			Action	DRS
	Analysi_by_Maxquant.zip	Other
	WT_PLC_20200722.raw	Raw
	WT_PLC_20200722_2.raw	Raw
	WT_PLC_20200722_3.raw	Raw
	WT_THLE3_20200722.raw	Raw

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Label-free proteomic analysis of the HCC secretome and compared the protein profiles of human PLC liver cancer cells with that of human THLE3 hepatocytes secreted in conditioned medium

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