11 of MBOAT proteins (MBOAT1, MBOAT2, HHATL, GOAT, LPCAT3, MBOAT7, SOAT1, SOAT2, HHAT, DGAT1,PORCN) abnormal change has been reported in many tumors, including chronic lymphocytic leukemia (CLL), pancreatic ductal adenocarcinoma(PDAC), prostate cancer, clear cell renal carcinoma (ccRCC), Glioblastoma(GBM), breast cancer and liver hepatocellular carcinoma(LIHC)17–23. Although the function of some MBOAT proteins in the tumorigenesis and prognosis of some cancers has been partially reported, further bio- informatics analysis of liver hepatocellular carcinoma has yet to be conformed. Thid study is the first time to explore the mRNA expression and prognostic worth (OS, PFS, RFS, and DSS of 11 of MBOAT family genes in liver hepatocellular carcinoma. We hope that our researches will help to practible knowledge, enhance treatment designs, and improve the accuracy of prognosis for patients with liver hepatocellular carcinoma.
MBOAT1 genes overexpression were significantly associated with a reduced risk of disease progression with HR = 2.1, 95% CI: 1.1–3.7, P = .018, forcing the afore-mentioned genes in a Cox multivariate model together with IGHV mutational status, indicating that MBOAT1 can surrogate molecular markers for IGHV mutational status in chronic lymphocytic leukemia for predicting time to first treatment.17 We revealed that the expression of MBOAT1 was higher in liver hepatocellular carcinoma than in normal tissues by Oncomine datasets and The Cancer Genome Atlas datasets. Although MBOAT1 expression was not correlated with the clinical features of the patients with hepatocellular carcinoma. By the Kaplan- Meier Plotter, we found the prognostic value of MBOAT1 in patients with hepatocellular carcinoma. A high MBOAT1 expression was highly associated with poor OS, PFS, RFS, and DSS in all of the patients with hepatocellular carcinoma followed up for 120 months.
Until now, little was known about the expression and role of MBOAT2 in hepatocellular carcinoma.Zhouxiaoxiao et al.41 reported that Circ-MBOAT2 knockdown represses tumor progression and glutamine catabolism by miR-433-3p/GOT1 axis in pancreatic cancer. Moreover, Tang Xiaolong et al.42 reported that CircMBOAT2 is highly expressed in both colorectal cancer (CRC) tissues and serum samples, and has a relationship with tumor stage, which suggested that MBOAT2 might be a novel potential biomarker of CRC. In our study, the expression of MBOAT2 in hepatocellular carcinoma tissues was higher than in normal tissues. What’s more, MBOAT2 expression was correlated with tumor stage in patients with liver hepatocellular carcinoma. However, MBOAT2 expression was not significantly correlated with poor OS, PFS, RFS, and DSS in all of the patients with hepatocellular carcinoma.
HHATL (Gup1p), an O-acyltransferase, is required for several cellular processes that are related to apoptosis development, such as rafts integrity and stability, lipid metabolism43. We demonstrated that the expression of HHATL in hepatocellular carcinoma tissues has no difference than that in normal tissues, and this expression has no relationship with tumor stage in patients with hepatocellular carcinoma. It’s worth noting that a low 3 expression was significantly correlated with poor OS, PFS, RFS, and DSS in all of the patients with hepatocellular carcinoma, which seemed that function of HHATL was not an oncogene.
= 1.214)38, but the mRNA level and the clinicopathological
MBOAT4, a member of the MBOATs super-family, is also named as as ghrelin O-acyltransferase (GOAT). Gualillo Oreste et al. found drugs that inhibit GOAT might be able to prevent diet-induced obesity and might be an effective therapy for type- 2 diabetes.44 In our report, we demonstrated that there was no difference in the expression of MBOAT4 in hepatocellular carcinoma tissues than in normal tissues, meanwhile this expression has relationship with tumor stage in patients with hepatocellular carcinoma.
LPCAT3 regulated intestinal stem cells and progenitor cells by stimulating cholesterol biosynthesis; increasing cholesterol in the diet or through genetic manipulation promoted tumorigenesis45. LPCAT3 maintains systemic lipid homeostasis by regulating lipid absorption in intestine, lipoprotein secretion, and de novo lipogenesis in liver. Mounting evidence also suggests that changes in LPCAT activity may be potentially involved in pathological conditions, including nonalcoholic fatty liver disease and cancer46. Moreover, Rong Xin et al.47 discovered that promotion of Lpcat3 activity ameliorates endoplasmic reticulum (ER) stress induced by saturated free fatty acids in vitro or by hepatic lipid accumulation in vivo. Conversely, Lpcat3 knockdown in liver exacerbates ER stress and inflammation. In this report, we demonstrated that transcriptional levels of Lpcat3 in patients with liver hepatocellular carcinoma was higher expressed in Chen Liver(fold change
parameters was not markedly correlated. A higher Lpcat3 expression was significantly correlated with poor PFS and RFS in all of the patients with hepatocellular carcinoma.
In a human biopsied NAFLD cohort, MBOAT7 rs641738C > T is reported associated with fibrosis (p0.004) independent of the presence of histological inflammation48. However, the prognostic role of MBOAT7 in hepatocellular carcinoma has yet to be investigated. In this report, we demonstrated that the transcriptionnal levels of MBOAT7 in hepatocellular carcinoma tissues was higher in three datasets than that in normal tissues, but this expression was not correlated with tumor stage in patients with hepatocellular carcinoma. A higher MBOAT7 expression was correlated with poor OS, DSS, PFS, and RFS in all of the patients with hepatocellular carcinoma, with significantly difference, respectively.
SOAT1 was known to play important role in hepatocellular carcinoma progression, and is associated with more advanced tumors with poor outcomes. Inhibition of SOAT1 suppresses Glioblastoma Growth via blocking SREBP-1-Mediated Lipogenesis49. Genetic targeting of SOAT1 impairs cell proliferation in vitro and tumor progression in vivo and reveals a mevalonate pathway dependency in p53 mutant PDAC cells that have undergone p53 loss of heterozygosity (LOH)50. Some new cholesterol metabolic molecules such as SOAT1, SQLE, and NPC1 have recently
emerged as promising drug targets for cancer treatment51. We found the transcriptional level of SOAT1 increased in all six of the eight databases. A high SOAT1 expression was obviously related with poor OS and DSS in all of the patients with hepatocellular carcinoma, which seemed consistent with the role of SOAT1 as a tumor promoter.
SOAT2(ACAT2) is reported expressed in several tumors. Pramfalk C et al 52 showed that HNF4alpha, directly or indirectly (via HNF1alpha), can bind to the ACAT2 promoterreported via ChIP assays and protein-to-protein interaction studies. Thus lower levels of esterified cholesterol in VLDL- and LDL-particles in patients with MODY1 may at least in part-be attributable to lower ACAT2 activity in these patients. Other data indicate that leptin may enhance the proliferation, migration and invasion of breast cancer cells via ACAT2 up- regulation through the PI3K/AKT/SREBP2 signaling pathway. Therefore, the leptin/ACAT2 axis may represent an attractive therapeutic target for breast cancer53. In our report, the expression of SOAT2 in hepatocellular carcinoma tissues was higher than that in normal tissues. However, SOAT2 expression was not correlated with tumor stage in patients with hepatocellular carcinoma.
Up to now, little was known about the expression and function of HHAT in hepatocellular carcinoma. While Asciolla James J et al.54reported that HHAT serves a dual function as a palmitoyl acyltransferase and a conduit to supply palmitoyl-CoA to the luminal side of the ER. Regan Joseph L et al using small- molecule inhibitors and RNAi against HHAT, demonstrate that non-canonical Hedgehog signaling is a positive regulator of WNT signaling and required for colon CSC survival55. In our data HHAT were significantly upregulated in patients with hepatocellular carcinoma in all eight datasets, and high OS, RFS, PFS and DSS.
Figure 6. MBOAT Gene Expression and Mutation Analysis in liver Hepatocellular Carcinoma (cBioPortal)
(A、B)MBOAT gene expression and mutation analysis in liver Hepatocellular Carcinoma (cBioPortal).
PORCN is a membrane-bound O-acyltransferase that is required for and dedicated to palmitoylation of Wnt ligands, a necessary step in the processing of Wnt ligand secretion56. PORCN inhibitors that block Wnt secretion have proven effective in Wnt- addicted preclinical cancer models and are in clinical trials57. We found the mRNA expression of PORCN in hepatocellular carcinoma tissues was higher than that in normal tissues. While, PORCN expression has no relationship with tumor stage in patients with hepatocellular carcinoma. Corbet Cyril showed that upon TGF-β2 stimulation, PKC-zeta-mediated translocation of CD36 facilitates the uptake of fatty acids that are either stored as triglycerides in LD through PORCN or oxidized to generate ATP to fulfill immediate cellular needs56.
In this study, we roundly analyzed the expression and prognostic role of MBOATs in HCC, and we provided a deeply understanding of the heterogeneity and complecated of the molecular biological properties in hepatocellular carcinoma. Our report indicated that the increased expression of SOAT1, 2, and DGAT1 in HCC tissues might play a significantly function. High MBOAT1–3, 5, 7, and 8 expressions could also treated as molecular markers to identify high-risk sub-groups of patients with HCC. In this study, we suggested that MBOAT1–3, SOAT1, PORCN and DGAT1 were potential therapeutic targets for HCC, and transcriptional MBOAT4 and 6 were possible prognostic markers for the improvement of HCC survival and prognosticaccuracy.