Histidine ammonia lyase expression characteristics in primary liver cancer: hepatocellular carcinoma and cholangiocarcinoma.

[BACKGROUND] Histidine (His) ammonia Lyase (HAL) is a key rate-limiting enzyme that catalyzes the first reaction in the metabolism of histidine. Deficiencies in HAL lead to histidinemia, characterized by elevated levels of His in the blood and other body fluids. The level of HAL in these fluids is known to impact the sensitivity of cancer cells to certain chemotherapeutics by regulating His. However, the molecular role and impacts of HAL in the progression of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are unknown at present. Thus, we investigated the expression of HAL in HCC and CCA tumors.

[METHOD] The Cancer Genome Atlas (TCGA) database, quantitative real-time PCR (qRT-PCR), and immunoblot analysis were utilized to examine the expression of HAL in HCC and CCA patients.

[RESULTS] TCGA analysis revealed a significant downregulation of HAL mRNA expression in HCC and CCA tumor tissues compared with normal tissues (p < 0.0001). Our qRT-PCR and immunoblot analysis demonstrated a significant decrease in both HAL mRNA (HCC, n = 9, p < 0.05; CCA, n = 7, p < 0.05) and protein levels (HCC, 91.7%, 22/24; CCA, 92.9%, 13/14) in both HCC and CCA tumor tissues compared with adjacent non-tumor liver/ bile duct tissues across the majority of patient samples analyzed. The protein expression pattern aligns with the mRNA findings, indicating that HAL downregulation occurs at both transcriptional and protein levels.

[CONCLUSION] Our data evinced the relevance and significance of HAL in the tumorigenesis of HCC and CCA. These findings suggest that HAL and its metabolic derivatives can be developed as a potential prognostic and diagnostic biomarker as well as therapeutics for HCC and CCA.