The Autophagy-Related Marker LC3 Can Predict Prognosis in Human Hepatocellular Carcinoma

Abstract

BackgroundDefects of autophagy and endoplasmic reticulum (ER) stress are related to many diseases and tumors. However, only a few studies have examined hepatocellular carcinoma (HCC) as related to these processes. Therefore, in this study, we investigated the expression and extent of autophagy and ER stress-related markers in HCC and their influence on clinical characteristics and prognosis for each protein.MethodologyThe expression of autophagy-related markers (LC3 and Beclin-1) and ER stress-related markers (GRP78 and CHOP) was analyzed by immunohistochemistry on tissues from completely resected specimens of 190 HCC patients. Their influence on clinicopathologic features and prognosis were evaluated using the chi-square test and Kaplan-Meier analysis. Correlations of each protein were determined by Spearman's correlation analysis. Principal FindingsLC3 expression was not correlated with TNM, BCLC stage, or Edmonson-Steiner grading, whereas it was correlated with longer overall survival (OS) (p = 0.039) and tended to be related with longer time to recurrence (TTR) (p=0.068) although it did not show statistical significance. Multivariate analysis indicated that LC3 expression was a significantly independent prognostic factor of OS (HR, 0.42; 95% CI, 0.22-0.80; p-value=0.009) and TTR (HR, 0.54; 95% CI, 0.33–0.90; p=0.017). Expression of LC3 in advanced stages of TNM (III) (p=0.045) and Edmonson-Steiner Grades (III and IV) (p=0.043) was correlated with longer survival, but not in the early stages. A positive correlation was not observed between the expression of autophagy-related markers and ER stress-related markers.ConclusionOur results suggest that the expression and extent of LC3 might be a strong prognostic factor of HCC, especially in patients with surgical resection.

SCD1 negatively regulates autophagy-induced cell death in human hepatocellular carcinoma through inactivation of the AMPK signaling pathway

“…We further observed that the inhibition of SCD1 resulted in cell death accompanied by a marked increase According to current reports, autophagy is a dual regulator in cancer initiation and development [49; 50; 51], including in HCC [18; 19; 20; 21]. In this study, we found that LC3 protein expression was significantly decreased in HCC and that positive LC3 expression was correlated with good clinical results in HCC patients, which is consistent with findings recently reported by another group [23]. Moreover, the results reported by Mathew et al [52] provide evidence to demonstrate that autophagy-defective tumor cells exhibit P62 accumulation, which promotes tumorigenesis.…”

“…A scoring system was applied as previously described [23]. In brief, a staining index for each case was determined by multiplying the score for the intensity of cytoplasmic staining (none staining = 0, weak = 1, moderate =2, strong = 3) with the score for the proportion of stained tumor cytoplasm (none = 0, <10% = 1, 10-50% = 2, >50% = 3).…”

“…In addition, Beclin-1 expression is decreased in human HCC tissues and is positively associated with longer time to recurrence and longer overall survival [22]. Similarly, the downregulation of LC3 expression is detected in HCC, and LC3 expression is correlated with a longer overall survival of HCC patients, particularly those in advanced stages, suggesting that LC3 is an independent predictor of prognosis in patients with HCC [23]. Therefore, understanding the significance of autophagy may contribute to the identification of a novel therapeutic target for the prevention and treatment of HCC.…”

Annexin A6 protein is downregulated in human hepatocellular carcinoma

“…This suppression is attributed to low levels in grade 2 compared to grade 1 HCC. Higher grade is associated with hepatocyte dedifferentiation and a worse prognosis [43,44]. Further research has to evaluate a potential prognostic value of AnxA6 in liver cancer.…”

Hypoxia-induced autophagy in hepatocellular carcinoma and anticancer therapy

“…[28] and associated with longer OS in advanced stage of HCC. [29] In addition, LC3 is an independent predictor of HCC recurrence after surgery only in the context of large tumors. [28] These data support aberrant autophagy activates tumorigenesis.…”