Abstract
Exploring the function of chaperone-mediated autophagy (CMA) in cancer has promoted progress in cancer treatment through the regulation of CMA pathways. However, CMA status and function in hepatocellular carcinoma (HCC) by focusing on the regulatory role of lyso-some-associated membrane protein type 2a (Lamp2a) remain to be clarified. We examined Lamp2a in a normal human liver cell line, 6 HCC cell lines, 10 normal liver samples as well as 42 HCC tissue and para-tumor tissues samples, and then validated it in 228 HCC patients to assess the relationship between Lamp2a and clinical prognosis. Gain and loss of Lamp2a function were also explored in HCC cell lines and xenograft models. Significantly lower level of Lamp2a expression was found in HCC cells and tissues compared with normal hepatic cells, para-tumor tissues and normal livers. Although no differences in HCC cell morphology or function were observed in relation to Lamp2a expression under normal culture or short-term starvation conditions, Lamp2a blockage significantly inhibited HCC cell viability under prolonged starvation. Critically, Lamp2a is required for HCC xenograft growth invivo by helping cells to avoid apoptosis and promoting cell proliferation. Furthermore, a significant correlation between Lamp2a expression and tumor size or cumulative recurrence was uncovered in HCC patients. Collectively, the present study shows that impaired Lamp2a expression in HCC contributes to tumor cell viability and promotes tumor growth and recurrence. Targeting chaperone-mediated autophagy through Lamp2a may also imply a potentially novel treatment strategy for HCC.
Highlights
Hepatocellular carcinoma (HCC) is a major cause of cancer-related death [1]
Among the HCC cell lines, lysosome-associated membrane protein type 2a (Lamp2a) expression levels were high in Huh7, intermediate in MHCC97L, MHCC97H and HepG2, and low in Hep3B and HCCLM3 cells, which did not correlate with their malignancy or invasiveness
We further evaluated the effect of Lamp2a expression in HCC cells in paired isogenic HCC cell lines in which Lamp2a expression was modified by RNA interference or cDNA transfection (Fig. 1B)
Summary
Hepatocellular carcinoma (HCC) is a major cause of cancer-related death [1]. It is highly resistant to available chemotherapeutic agents, leaving HCC patients with no effective therapeutic option and a poor prognosis. Cell death has been attributed to unrestrained autophagy, increasing data indicate that autophagy may function as an important tumor-protective mechanism in HCC [4,5]. Understanding of CMA activities under different pathological and physiological conditions is increasing day by day, especially in cancer [10]. Activation during prolonged starvation is associated with increased levels of lysosome-associated membrane protein type 2a (Lamp2a) at the lysosomal membrane, which represents a limiting step in this pathway [10,12]. Lamp2a in the lysosomal membrane acts as a receptor of substrate proteins for CMA, and Lamp2a in the lysosomal membrane have been shown to correlate directly with CMA activity under pathological and physiological conditions [13,14,15]
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