Axl and autophagy LC3 expression in tumors is strongly associated with clinical prognosis of hepatocellular carcinoma patients after curative resection.

Chia‐Chang Hsu,Yaw‐Sen Chen,Pei‐Min Hsieh,Jee‐Fu Huang,Wan‐Long Chuang,Chih‐Wen Lin,Hung‐Yu Lin,Yao‐Li Chen,Gin‐Ho Lo,Ming‐Lung Yu,Chia‐Yen Dai

doi:10.1002/cam4.2229

Abstract

BackgroundThe role of Axl and LC3 as predictors of tumor recurrence and overall survival (OS) after hepatocellular carcinoma (HCC) resection remains unclear.MethodsWe retrospectively included 535 HCC patients who underwent hepatectomy from 2010 to 2014 in this study. Axl and the autophagy‐related marker LC3 were immunohistochemically assessed in tumors.ResultsAxl expression was significantly associated with advanced clinicopathological features, including cirrhosis, microvascular invasion, macrovascular invasion, tumor size, BCLC stage, recurrence, and mortality. HCC recurrence occurred in 245 patients, and 219 patients died. The 5‐year cumulative incidences of HCC recurrence and OS rate after HCC resection were 53.3% and 58.8%, respectively. In the Cox proportional analyses, high Axl expression and high LC3 expression were significantly associated with HCC recurrence (hazard ratio [HR]: 3.85, 95% confidence interval [CI]: 2.95‐5.02, P < 0.001; and HR: 0.38, 95% CI: 0.26‐0.55, P < 0.001, respectively). In addition, HCC recurrence (HR: 2.87, 95% CI: 2.01‐4.01, P < 0.0001), microvascular invasion (HR: 1.85, 95% CI: 1.08‐3.19, P = 0.026), hepatitis B virus‐related HCC (HR: 1.77, 95% CI: 1. 21‐2.56, P = 0.003), high Axl expression (HR: 1.66, 95% CI: 1.41‐1.97, P < 0.0001), antiviral therapy (HR: 0.54, CI: 0.38‐0.76, P < 0.001) and LC3 expression (HR: 0.41, 95% CI: 0.28‐0.58, P < 0.001) were significantly associated with mortality. Furthermore, patients with a combination of high Axl and low LC3 expression had the highest risk of HCC recurrence (HR: 6.53, 95% CI: 4.11‐10.4, P < 0.001) and mortality (HR: 6.66, 95% CI: 4.07‐10.9, P < 0.001). In patients with high Axl, low LC3, and combined high Axl and low LC3 expression, the 5‐year cumulative incidences of HCC recurrence and OS rate were 77.9%, 73.3%, and 90.0% and 28.8%, 26.7%, and 16.8%, respectively.ConclusionHigh Axl expression in tumors is associated with aggressive tumor behavior and worse clinical outcomes. Furthermore, the combination of high Axl and low LC3 expression significantly predicts poorer prognosis for HCC patients who underwent hepatectomy.

Highlights

Hepatocellular carcinoma (HCC) is the third common cause of cancer‐related death in the world.[1,2] In Taiwan, viral‐ and alcohol‐related cirrhosis frequently result in hepatocellular carcinoma (HCC).[3]
High Axl expression in tumors was significantly associated with advanced clinicopathological features, high HCC recurrence rates, and low overall survival (OS) rates
Low LC3 expression in tumors was significantly correlated with high HCC recurrence and low OS rates

Summary

| INTRODUCTION

Hepatocellular carcinoma (HCC) is the third common cause of cancer‐related death in the world.[1,2] In Taiwan, viral‐ and alcohol‐related cirrhosis frequently result in HCC.[3]. Reichl et al reported that high serum levels of soluble Axl are correlated with vascular involvement and lymph node metastasis, and the serum level of soluble Axl is a potential biomarker for the early diagnosis of HCC and the early prediction of HCC recurrence.[14]. Several studies showed that Axl may be a negative predictor for HCC patients, and high Axl expression was positively associated with differentiation, lymph node metastasis, higher recurrence rates, and lower survival rates in HCC patients.[16,17]. Axl expression was associated with increased tumor invasion and predicted a worse prognosis for HCC patients undergoing resection.[18]. Our previous studies showed that high LC3 expression in the liver and tumor microenvironments is strongly correlated with higher OS and lower HCC recurrence.[7,8]. Whether Axl expression is associated with clinical prognosis in HCC patients remains largely unknown. We investigate the impact of Axl and LC3 expression on tumor recurrence and OS in a large cohort of HCC patients who underwent curative resection

| MATERIALS AND METHODS

| RESULTS

Findings

| DISCUSSION