Tumor-suppressive role of HACE1 in hepatocellular carcinoma and its clinical significance

Abstract

An increasing body of evidence suggests that downregulation or deletion of HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1) gene plays an important role in the occurrence, invasion and metastasis process in many human malignancies and is closely related to prognosis. However, sparse evidence exists concerning the precise function and clinical significance of HACE1 in hepatocellular carcinoma (HCC). In the present study, we investigated the expression pattern of HACE1 in HCC tissues and cell lines, and determined the potential functions of HACE1 in HCC cell lines and evaluated the relationships between HACE1 expression and clinicopathological characteristics. Protein and mRNA expression levels of HACE1 in human HCC tissues and cell lines were examined by western blot analysis, quantitative real‑time polymerase chain reaction and immunohistochemical (IHC) analyses. IHC was used to analyze the correlations between HACE1 expression and clinicopathological features. HACE1 was upregulated in SMCC7721 cells by transfection with pcDNA3.1-HACE1 and Huh7 cells were transfected with siRNA targeting HACE1 for downregulation. Cell Counting Κit-8, Transwell and wound healing assays were performed to investigate the effects of the overexpression and knockdown of HACE1 on cellular proliferation and migration. The results revealed that HACE1 expression was lower in the HCC tissues and cell lines at the mRNA and protein levels compared to levels noted in the matched non‑tumor tissues and the normal liver cell line L02. Knockdown of HACE1 in Huh7 cells accelerated cell proliferation and migration (P<0.05), and overexpression of HACE1 in SMCC7721 cells was found to decrease the capacity for proliferation and migration (P<0.01). The results of IHC suggested that the HACE1 expression level was closely related to the serum AFP level, tumor differentiation and vascular invasion (P<0.05). Patients with low HACE1 expression levels exhibited poorer overall survival and HACE1 was found to be an independent prognostic factor for survival. In conclusion, as a tumor suppressor, HACE1 may be a valuable prognostic biomarker and potential therapeutic target for HCC treatment.

Overexpression of HACE1 in gastric cancer inhibits tumor aggressiveness by impeding cell proliferation and migration

“…HACE1 was found low expressed in previous studies about breast cancer , colorectal cancer , liver cancer and leukemia . In this study, we also spotted a significant down‐regulation of HACE1 in gastric cancer tissues compared with their adjacent normal tissues.…”

Demethylation of the HACE1 gene promoter inhibits the proliferation of human liver cancer cells

“…A previous study reported that HACE1 has a tumour-suppressive role in hepatocellular carcinoma (5). To evaluate whether CRISPR-Cas-induced upregulation of HACE1 resulted in physiologically relevant effects, the proliferation of Hep3B and HepG2 cells was detected by MTT assays at 24 and 48 h post transfection.…”

“…The majority of liver cancer cases are diagnosed at an advanced or unresectable stage; therefore, novel therapeutic strategies and therapeutic targets are required. Current studies mainly focus on the pathogenic genes and molecular mechanisms involved in liver cancer (5,6).…”

“…HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1) is a member of the HECT domain-containing E3 ligase family and was originally identified to be associated with the occurrence of Wilms' tumour (7). Furthermore, additional studies revealed that lower expression or mutations of HACE1 are associated with numerous types of human malignant tumours, including breast cancer, colorectal cancer, lung cancer, liver cancer, gastric cancer and lymphoma (5,(8)(9)(10)(11)(12), which suggests that HACE1 functions as a tumour suppressor. Additional research concerning HACE1 has focused on a variety of downstream pathways; for example, HACE1 has been reported to act as a tumour suppressor by ubiquitinating optineurin (OPTN) and activating selective autophagy (10).…”

Bayesian Cox Proportional Hazards Model in Survival Analysis of HACE1 Gene with Age at Onset of Alzheimer's Disease

“…The HACE1 is expressed in brain, heart, lung, kidney, testis, and ovary [13,15]. Several studies have implicated that HACE1 is a candidate chromosome 6q21 tumor suppressor gene involved in multiple cancers [16–18]. Recently, it has been reported that HACE1 gene may play a role in neurodegeneration [19] and autophagy pathway [20]; while HACE1 mutations are involved in an autosomal recessive neurodevelopmental disorder [21], and glutamine addiction [22].…”