Aldehyde dehydrogenase 1 (ALDH1) isoform expression and potential clinical implications in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most prevalent and life-threatening malignancies worldwide. There are few diagnostic and prognostic biomarkers and druggable targets for HCC. Aldehyde dehydrogenase 1 (ALDH1) is a marker of stem cells in a variety of cancers, but the mRNA levels and prognostic value of ALDH1 isoforms in HCC patients remain unknown. In the present study, gene ontology annotation of the ALDH1 family was performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID), and the gene pathway analsis was performed using GeneMANIA software. The initial prognostic value of ALDH1 expression in 360 HCC patients was assessed using the OncoLnc database. The expression levels of ALDH1 isoforms in normal liver tissues and clinical specimens of cancer vs. normal control datasets were determined using the GTEx and Oncomine databases, respectively. We then analyzed the prognostic value of ALDH1 expression in 212 hepatitis B virus (HBV)–related HCC patients using the GEO database. We found that the ALDH1 isoform showed high aldehyde dehydrogenase activity. The ALDH1A1, ALDH1B1, and ALDH1L1 genes encoded for the ALDH1 enzyme. High ALDH1B1 expression had protective qualities in HCC patients. Moreover, HBV–related HCC patients who showed high ALDH1L1 gene expression had a better clinical outcomes. In addition, high ALDH1A1 expression was associated with a 57–month recurrence–free survival in HBV-related HCC patients. High ALDH1B1 expression was protective for HCCs with multiple nodules and high serum alpha–fetoprotein (AFP) level. Furthermore, high serum AFP levels contributed to lower ALDH1L1. ALDH1A1, ALDH1B1, and ALDH1L1, all of which were considered promising diagnostic and prognostic markers as well as potential drug targets.

Aldehyde Dehydrogenase, Liver Disease and Cancer

“…In terms of prognosis, a lower ALDH2 level was a poor prognosticator following primary resection, coincident with older age, embolus, larger tumor size, extrahepatic metastasis and microvascular invasion in HCC patients [13]. Furthermore, a correlation of higher ALDH1B1 and ALDH1L1 gene expression with better clinical outcomes was noted in HBV-related HCC patients [16,93].…”

“…As antioxidants, ALDHs can also decrease immunogenic cell death and limit tumor immunity by reducing endoplasmic reticulum stress and ROS production [98]. As reported, ALDH1B1 activity was downregulated in liver cancer tissues compared to normal liver tissue, and the reduced ALDH1B1 activity was considered protective in HCC patients through its influence on the oxidation of short-chain aldehydes including acetaldehyde and propionaldehyde [16], and its protective against alcohol-induced hepatocellular proliferation and hepatic neoplasm in mice [99]. In addition, ALDH1L1, which is also reduced in HCC, also can suppress cancer cell proliferation by depleting intracellular 10-formyltetrahydrofolatedehydrogenase, which is required for de novo purine biosynthesis [100,101].…”

“…Cytosolic ALDH1A1 plays a role acetaldehyde oxidation and alcohol preference through mediating a γ-aminobutyric acid synthesis pathway [14]. ALDH1B1, which is expressed at high levels in the liver and intestine epithelium, is an ALDH1 isoform that demonstrates high affinity to acetaldehyde only secondary to ALDH2 and catalyzes various aldehyde substrates of acetaldehyde and derivatives of lipid peroxidation [15,16] (Table 1).…”

Update of ALDH as a Potential Biomarker and Therapeutic Target for AML

“…The aldehyde dehydrogenase (ALDH) is a group of intracellular enzymes that participate in cellular detoxification, differentiation, and drug resistance by oxidation of cellular aldehydes [ 10 ]. To date, 19 ALDH genes are identified within the human genome.…”

The prognostic roles of circulating ALDH1+ tumor cell in the patients with non-small cell lung cancer

“…CTCs included valuable information about tumor invasiveness, recurrence, and drug resistance [ 5 ]. Aldehyde dehydrogenase 1 (ALDH1) is a detoxifying enzyme that oxidizes aldehyde into carboxylic acid and converts retinol into retinoic acid [ 6 ]. It has been found in various tumors, including NSCLC, breast cancer, and gastric cancer [ 7–9 ].…”