Cancer-Testis Antigen LDH-C4 in Tissue, Serum, and Serum-Derived Exosomes Serves as a Promising Biomarker in Lung Adenocarcinoma

Abstract

ObjectiveAs a cancer-testis antigen (CTA), human lactate dehydrogenase C4 (LDH-C4) enzyme protein encoded by the LDHC gene has been reported to be involved in the occurrence and development of various malignancies, while its expression and clinical significance in lung adenocarcinoma (LUAD) remain unclear. This study aims to investigate the expression of LDH-C4 in LUAD and its diagnostic and prognostic value.MethodsThe mRNA and protein levels of LDH-C4 in LUAD and adjacent normal tissues were analyzed based on the UALCAN database, and the prognostic significance was assessed using the LOGpc database. The LDHC mRNA level in serum and serum secretion of LUAD patients was determined by quantitative real-time PCR (qRT-PCR). Based on the high-throughput LUAD tissue chip combined with immunohistochemistry (IHC), the protein level of LDH-C4 in LUAD tissues was measured, and its correlation with clinicopathological features and prognosis was analyzed.ResultsLDHC expression was upregulated in LUAD, which was related to the clinical stage and poor prognosis of patients. The positive rates of LDHC mRNA expression in serum and exosome of LUAD patients were 78.3% and 66.7%, respectively. The area under the curve (AUC) of serum and exosomal LDHC in the diagnosis of LUAD was 0.8121 and 0.8925, respectively. The expression of LDHC in serum and serum-derived exosomes from LUAD patients was negatively correlated with medical treatment and positively correlated with the recurrence of LUAD. The positive expression rate of LDH-C4 in LUAD tissues was 96.7% (89/92), which was significantly higher than that in adjacent normal tissues 22.6% (19/84) (p < 0.001). The median overall survival (OS) time of patients with a high expression of LDH-C4 was significantly shorter than that of patients with low expression (34 months versus 62 months) (p = 0.016). Further relative risk analysis exhibited that the expression of LDH-C4 was an independent prognostic factor of OS in patients with LUAD.ConclusionsLDHC/LDH-C4 expression was upregulated in LUAD, and LDH-C4 could be used as a molecular indicator of the prognosis of LUAD. Serum and serum-derived exosomes of LDHC can be used as an important biomarker for the diagnosis, efficacy evaluation, and recurrence monitoring of LUAD.

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“…Available bioinformatics analyses can be a powerful tool for identifying biomarkers and therapeutic targets related to tumour progression and treatment. Previous studies have shown that novel serum biomarkers, including serum exosomes ( 27 – 29 ) and serum CEA ( 30 – 33 ), are good predictors of prognosis in lung adenocarcinoma. In addition, serum biomarkers related to inflammatory response are also good predictors of lung adenocarcinoma prognosis ( 34 , 35 ).…”

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“…The pan-cancer expression of LDHC /LDH-C4 has been assessed, and the results of IHC based on high-throughput tissue microarray analyses suggest the highest positivity rate of LDH-C4 in LUAD (96.7%) ( 63 ), followed by breast cancer (BC) (91.55%) ( 36 ), and hepatocellular carcinoma (HCC) (55.84%) ( 37 ). LDHC is expressed in serum and serum exosomes of tumor patients, with serum LDHC positivity rates of 91.66%, 68%, and 65% in BC ( 36 ), HCC ( 37 ), and LUAD ( 63 ), respectively. Serum-sourced exosomal LDHC in BC and HCC also yield comparable positivity rates as those in the serum ( 36 , 37 ).…”

“…However, LDHC was a protective factor for prognosis in HNSCC and CESC ( Figures 3A, B ). In LUAD ( 63 ), LDH-C4 protein was significantly associated with TNM tumor status, and patients with high LDH-C4 expression had a worse prognosis than those with low/negative expression. Similar results were observed in HCC ( 37 ) and BC ( 36 ).…”

“…LDHC mRNA has been detected in serum and serum-derived exosomes of patients with BC ( 36 ), HCC ( 37 ), and LUAD ( 63 ), and the source may be related to vesicle encapsulation of tumor cells and release of necrotic tumor cells into the peripheral blood. The AUCs of serum LDHC for BC ( 36 ), HCC ( 37 ), and LUAD ( 63 ) reached 0.9587, 0.8382, and 0.8121, respectively, whereas those of serum-sourced LDHC for BC, HCC, and LUAD reached 0.9464, 0.9451, and 0.8925, respectively, higher than the corresponding values for serum LDHC . These data indicate that LDHC is a promising novel non-invasive marker for tumor diagnosis.…”