Decreased Expression of Heat Shock Protein 20 in Colorectal Cancer and Its Implication in Tumorigenesis

Abstract

Heat shock protein 20 (HSP20), which is a member of the small heat shock protein family, is known to participate in many pathological processes, such as asthma, intimal hyperplasia, and insulin resistance. However, the function of HSP20 in cancer development is not yet fully understood. In this study, we identified HSP20 as a down-regulated protein in 20 resected colorectal cancer (CRC) specimens compared with their paired normal tissues. Because HSP20 proteins were barely detectable in HCT-116 cells (a human colorectal cancer cell line), recombinant adenovirus encoding HSP20 (Ad-HSP20) was used to induce HSP20 overexpression in HCT-116 cells. Infection of Ad-HSP20, but not control adenovirus (Ad-GFP), reduced viability, and induced massive apoptosis in a time-dependent manner. The forced expression of HSP20 enhanced caspase-3/7 activity and down-regulated the anti-apoptotic Bcl-xL and Bcl-2 mRNA and protein levels. In addition, immunohistochemical analysis of 94 CRC specimens for HSP20 protein showed that reduced HSP20 expression was related to advanced TNM stage, lymph node metastasis, and tumor recurrence. Our study shows, for the first time, that expression of the HSP20 protein has a pro-death role in colorectal cancer cells. Therefore, HSP20 may have value as a prognostic tumor marker and its overexpression might be a novel strategy for CRC therapy.

Integrated analysis of DNA methylation profiling and gene expression profiling identifies novel markers in lung cancer in Xuanwei, China

“…Upregulation of HSP20 in human hepatocellular carcinoma cells can inhibit cell proliferation via suppression of the AKT signaling pathway [ 42 ], inhibit TGFα-induced migration and invasion via suppression of the JNK signaling pathway [ 37 ], and stimulate the caspase cascade through direct association with Bax [ 41 ]; HSP20 upregulation also suppresses hepatocellular carcinoma progression by downregulating TNFα-stimulated intracellular signaling [ 38 ]. Downregulation of HSP20 was observed in colorectal cancer specimens compared with their paired normal tissues and was related to advanced TNM stage, lymph node metastasis, and tumor recurrence [ 39 ]. Overexpression of HSP20 in HCT-116 human colorectal cancer cells induced massive apoptosis in a time-dependent manner by enhancing caspase-3/7 activity and downregulating mRNA and proteins levels of anti-apoptotic Bcl-xL and Bcl-2 [ 39 ].…”

“…Downregulation of HSP20 was observed in colorectal cancer specimens compared with their paired normal tissues and was related to advanced TNM stage, lymph node metastasis, and tumor recurrence [ 39 ]. Overexpression of HSP20 in HCT-116 human colorectal cancer cells induced massive apoptosis in a time-dependent manner by enhancing caspase-3/7 activity and downregulating mRNA and proteins levels of anti-apoptotic Bcl-xL and Bcl-2 [ 39 ]. In our study, HSPB6 was significantly hypermethylated and downregulated in most of the tumor tissues, suggesting that it plays a protective role in the onset of lung cancer in Xuanwei.…”

Small heat shock proteins in ageing and age-related diseases

“…Evading apoptosis is one of the major cancer traits, and since sHSPs have an extremely intricate role in the regulation of apoptosis, these proteins attracted scientific interest to confront carcinogenesis. sHSPs possess mainly antiapoptotic properties; however, pro-apoptotic features have also been reported (Acunzo et al 2012;Arrigo and Gibert 2014;Bakthisaran et al 2015;Guo et al 2015;Ju et al 2015;Mymrikov et al 2011;Zeng et al 2013). Interestingly, sHSPs interfere with both extrinsic (dependent on death ligands and receptors) and intrinsic (mitochondrial-mediated) apoptotic pathways.…”

Aloe-Emodin Induces Endoplasmic Reticulum Stress-Dependent Apoptosis in Colorectal Cancer Cells

“…Colorectal cancer is one of the most prevalent and aggressive malignancies worldwide [ 1 ]. Most colorectal cancers are due to aging and lifestyle factors, which include diet, obesity, smoking, and lack of physical activity [ 2 ].…”