Beclin 1 Deficiency Correlated with Lymph Node Metastasis, Predicts a Distinct Outcome in Intrahepatic and Extrahepatic Cholangiocarcinoma

Abstract

Autophagy can be tumor suppressive as well as promotive in regulation of tumorigenesis and disease progression. Accordingly, the prognostic significance of autophagy key regulator Beclin 1 was varied among different tumors. Here, we detected the clinicopathological and prognostic effect of Beclin 1 in the subtypes of intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC). Beclin 1 expression level was detected by immunohistochemistry staining in 106 ICC and 74 ECC patients. We found that Beclin 1 was lowly expressed in 126 (70%) cholangiocarcinoma patients, consist of 72 ICC and 54 ECC. Moreover, the cholangiocarcinoma patients with lymph node metastasis (N1) had a lower Beclin 1 level than that of N0 subgroup (P=0.012). However, we did not detect any correlations between Beclin 1 and other clinicopathological features, including tumor subtypes, vascular invasion, HBV infection, liver cirrhosis, cholecystolithiasis and TNM stage. Survival analysis showed that, compared with the high expression subset, Beclin 1 low expression was correlated with a poorer 3-year progression-free survival (PFS, 69.1% VS 46.8%, P=041) for cholangiocarcinoma. Importantly, our stratified univariate and multivariate analysis confirmed that Beclin 1 lowly expressed ICC had an inferior PFS as well as overall survival than ECC, particularly than that of Beclin 1 highly expressed ECC patients. Thus, our study demonstrated that Beclin 1low expression, correlated with lymph node metastasis, and might be a negative prognostic biomarker for cholangiocarcinoma. Combined Beclin 1 level with the anatomical location might lead to refined prognosis for the subtypes of ICC and ECC.

Dihydroartemisinin induces apoptosis and autophagy‐dependent cell death in cholangiocarcinoma through a DAPK1‐BECLIN1 pathway

“…However, in DHA‐treated CCA cells this effect is reinforced by the reduced expression of BCL‐2 and the higher expression of BECLIN1. It is to be noted that BECLIN1 was found expressed at very low level in metastatic and therapy‐resistant CCAs . The sustained hyper‐regulation of autophagy induced by DHA eventually precipitated CCA cell death.…”

“…Autophagy, a lysosome‐mediated macromolecular degradation pathway, may exert a tumor suppressive function in CCA. In fact, low level of expression of the BECLIN1 autophagy protein was associated with metastatic CCAs and poor outcome in CCA patients …”

Effect of beclin 1 expression on the biological behavior and chemotherapy sensitivity of cervical cancer cells

“…There are a number of studies reporting that beclin 1 expression is associated with chemosensitivity (27,28). Beclin 1 may affect the chemosensitivity of cancer cells through several mechanisms.…”

Autophagy may occur at an early stage of cholangiocarcinogenesis via biliary intraepithelial neoplasia

“…There have been several studies addressing the expression of autophagy-related proteins in CC and its clinicopathological significance, such as for prognosis [17,18]; however, to the best of our knowledge, no study has dealt with the involvement of autophagy in premalignant lesions, BilIN and IPNB. Since the process of autophagy itself is completed within a short time, immunohistochemical granular expression of LC3 may indicate the accumulation of autophagic vacuoles due to induced and deregulated autophagy [14,15].…”

“…The involvement of autophagy in the process of cholangiocarcinogenesis via BilIN has not been studied, although several studies have reported the expression of autophagy-related proteins and its clinicopathological significance in CC [17,18]. We previously disclosed that cellular senescence participates in stepwise cholangiocarcinogenesis in the large bile duct (LBD) via BilIN [19]; that is, the expression of senescence-associated p16 INK4a occurs at an early stage, and then overexpression of EZH2 plays a role in the bypass/escape from senescence followed by the development of overt carcinoma [19].…”