3315

HSPB1

heat shock 27kDa protein 1;HSPB1;heat shock 27kDa protein 1

28 kDa heat shock protein|HSP 27|epididymis secretory protein Li 102|estrogen-regulated 24 kDa protein|heat shock 27 kDa protein|heat shock 27kD protein 1|heat shock protein beta-1|stress-responsive protein 27

7q11.23

protein-coding

The 25-kDa heat shock protein (Hsp25) is associated with various malignancies and is expressed at high levels in biopsies as well as circulating in the serum of breast cancer patients. In this study, we used RNA interference technology to silence the hsp25 gene in 4T1 breast adenocarcinoma cells, known as a poorly immunogenic, highly metastatic cell line. We demonstrate that transfection of 4T1 cells with short interference RNA-Hsp25 dramatically inhibits proliferation as compared with control transfected cells. In addition, we show that 4T1 cells transfected with short interference RNA-Hsp25 abrogates tumor migration potential by a mechanism that is in part due to the repression of matrix metalloproteinase 9 expression and a concomitant upregulation of its antagonist, tissue inhibitor metalloproteinase 1. Taken together, these findings provide a model system for the study of metastatic potential of tumors and are suggestive of an earlier unrecognized role for Hsp25 in tumor migration.

Previous studies have indicated that heat shock protein 27 (HSP27) had high correlation with the development and progression in several tumors. However, the roles of HSP27 in esophageal squamous cell carcinoma (ESCC) were uncertain. The aim in this study is to investigate the potential roles of HSP27 in the metastasis of ESCC. The expression of HSP27 in ESCC tissues and four human esophageal cancer cell lines were examined by immunohistochemistry and Western blotting, respectively. Wound healing assays, transwell assays, and in vivo assays were used to identify the differences of metastasis potential between normal and HSP27 overexpressed cells. HSP27 expression was downregulated in cancer tissue compared to the matched normal tissue. And the positive staining was mainly located in the cytoplasm. Statistical analyses showed that the expression of HSP27 in ESCC was significantly correlated with the tumor differentiation (P = 0.023), the patient's TNM stage (P = 0.013), lymph metastasis (P = 0.020), and distant metastasis (P = 0.017). HSP27 expression was significantly lower in highly metastatic cells than the less ones. The metastatic potentials of EC9706-H and EC109-H cells were higher than EC9706-L and EC109-L cells. In vitro and in vivo assays showed that overexpression of HSP27 in highly metastatic cells dramatically decreased their metastatic capacity. This study indicated that the expression level of HSP27 may be inversely correlated with the metastasis behavior of ESCC, and HSP27 may play an important role in this progression. HSP27 may be a potential molecular target for the therapy and prognosis of patients with ESCC.

The small heat shock protein 27 (Hsp27) is a molecular chaperone that is involved in a variety of cellular functions in cancer cells. The purpose of this research is to study Hsp27 in vitro metastatic behaviors of head and neck squamous cell carcinoma cells (HNSCC). The expression of Hsp27 in primary and metastatic cell lines derived from the primary HNSCC and a synchronous lymph node metastasis in the same patient was determined using real-time PCR and Western blotting. Proliferation of the primary and metastatic HNSCC cell lines was evaluated using the MTS proliferation assay. metastatic behavior was assessed using migration and invasion assays. SiRNA knockdown of Hsp27 was performed in the highly migratory metastatic HNSCC cell line. MTS assays showed that the primary (UM-SCC-22A) and metastatic (UM-SCC-22B) HNSCC have similar proliferation rates. However, UM-SCC-22B derived from the metastasis showed 2.3- to 3.6-fold higher migration ability and 2-fold higher invasion ability than UM-SCC-22A. Real-time PCR demonstrated that Hsp27 mRNA is 22.4-fold higher in metastatic UM-SCC-22B than primary UM-SCC-22A. Similarly, Western blotting showed that Hsp27 is rarely detectable in UM-SCC-22A whereas UM-SCC-22B expresses a 25-fold higher level of Hsp27 protein. SiRNA-mediated knockdown of Hsp27 in UM-SCC-22B reduced Hsp27 mRNA expression by nearly 6-fold and protein expression by 23-fold. Furthermore, siRNA knockdown of Hsp27 decreased metastatic behaviors of UM-SCC-22B by 3- to 4-fold in migration and 2-fold in cell invasion reducing cell invasion and migration to levels similar to the primary HNSCC UM-SCC-22A. These data indicate that Hsp27 may regulate metastatic potential of HNSCC cancer cells. Targeting Hsp27 may decrease metastasis in head and neck squamous cell cancer cells.

Ovarian cancer is the third most common gynecologic malignancy and the leading cause of death in gynecological cancer. Although the 5-year survival rate is increasing, peritoneal metastasis of ovarian cancer is still a problem because of no potential predictor. Heat shock proteins (HSPs) are a class of functionally related proteins that are highly expressed in many malignant cancers. Previous studies suggest high levels of HSP27 present in the serum of patients with ovarian cancer. In this study, we investigated whether the expression of HSP27 in epithelial ovarian cancer tissue was associated with peritoneal metastasis and whether HSP27 could be used as a potential predictor of peritoneal metastasis in epithelial ovarian cancer. Tissues from epithelial ovarian cancer with or without peritoneal metastasis were collected and the levels of HSP27 messenger RNA and protein determined by real-time polymerase chain reaction and Western blotting. Immunohistochemistry was used to determine the subcellular localization of HSP27. Immunohistochemistry images showed that HSP27 was highly expressed in the cytoplasm of epithelial cancer cells with peritoneal metastasis. Messenger RNA and protein levels of HSP27 were significantly increased in epithelial ovarian cancer with peritoneal metastasis compared with epithelial ovarian cancer without peritoneal metastasis. Higher expression of HSP27 correlated with poor clinical outcome. These data suggest that higher level of HSP27 was associated with peritoneal metastasis in epithelial ovarian cancer. Heat shock protein 27 may be a useful prognostic marker of poor survival and may provide a basis for the development of molecular therapeutics modulating this survival pathway.

The hepatocyte growth factor (HGF) also known as scatter factor activates cancer cell invasion and metastasis. We show that in ovarian cancer cells HGF induced the phosphorylation of the small heat shock protein of 27 kDa (HSP27) by activating the p38MAPK. HSP27 is increased in many cancers at advanced stage including ovarian cancer and associated with cancer resistance to therapy and poor patients survival. The phosphorylation of HSP27 regulates both its chaperone activity and its control of cytoskeletal stability. We show that HSP27 was necessary for the remodeling of actin filaments induced by HGF and that motility in vitro depended on the p38MAPK-MK2 axis. In vivo, HSP27 silencing impaired the ability of the highly metastatic, HGF-secreting ovarian cancer cells to give rise to spontaneous metastases. This was due to defective motility across the vessel wall and reduced growth. Indeed, HSP27 silencing impaired the ability of circulating ovarian cancer cells to home to the lungs and to form experimental hematogenous metastases and the capability of cancer cells to grow as subcutaneous xenografts. Moreover, HSP27 suppression resulted in the sensitization of xenografts to low doses of the chemotherapeutic paclitaxel, likely because HSP27 protected microtubules from bundling caused by the drug. Altogether, these data show that the HSP27 is required for the proinvasive and prometastatic activity of HGF and suggest that HSP27 might be not only a marker of progression of ovarian cancer, but also a suitable target for therapy.

Prostate cancer (PCa) is the most common form of cancer in American men. Mortality from PCa is caused by the movement of cancer cells from the primary organ to form metastatic tumors at distant sites. Heat shock protein 27 (HSP27) is known to increase human PCa cell invasion and its overexpression is associated with metastatic disease. The role of HSP27 in driving PCa cell movement from the prostate to distant metastatic sites is unknown. Increased HSP27 expression increased metastasis as well as primary tumor mass. In vitro studies further examined the mechanism of HSP27-induced metastatic behavior. HSP27 did not affect cell detachment, adhesion, or migration, but did increase cell invasion. Cell invasion was dependent upon matrix metalloproteinase 2 (MMP-2), whose expression was increased by HSP27. In vivo, HSP27 induced commensurate changes in MMP-2 expression in tumors. These findings demonstrate that HSP27 drives metastatic spread of cancer cells from the prostate to distant sites, does so across a continuum of expression levels, and identifies HSP27-driven increases in MMP-2 expression as functionally relevant. These findings add to prior studies demonstrating that HSP27 increases PCa cell motility, growth and survival. Together, they demonstrate that HSP27 plays an important role in PCa progression.