Heat shock protein 27 promotes cell proliferation through activator protein-1 in lung cancer

Abstract

Abstract. Heat shock protein 27 (HSP27) is an important regulator involved in the development of lung cancer. However, limited evidence exists concerning the underlying molecular mechanisms of its action. The results of the present study revealed that HSP27 was highly expressed in the lung cancer tissues of mice. In an in vitro model, the overexpression of HSP27 promoted cell proliferation, while HSP27 knockdown inhibited cell proliferation. HSP27 promoted cell proliferation in vitro by directly upregulating the expression of HSP27 target genes, which required the activation of the activator protein-1 (AP-1) signaling pathway. This was evaluated by the phosphorylation status of an important pathway component, c-Jun in lung cancer tissue and cells. These results suggested that HSP27 has a promotional role in lung cancer, and therefore indicated a novel mechanism involving lung cancer cell proliferation, which may underlie poor responses to therapy. Therefore, HSP27 may be a suitable therapeutic target for the treatment of lung cancer. IntroductionLung cancer is the leading cause of cancer-associated mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for ~85% of all mortalities associated with lung cancer. The overall five-year survival rate for patients remains poor (1-3). The poor prognoses of lung cancer patients primarily result from early relapse, metastasis and unsuccessful responses to treatment strategies, including surgery, chemotherapy and radiotherapy (4-6). In addition, the lack of effective prognostic biomarkers that are able to predict treatment response and prognosis affects treatment regimens and patient outcomes.Heat shock proteins (HSPs) are a large family of proteins that function as molecular chaperones under physiological conditions (7). The ability of radiofrequency ablation to induce the expression of HSPs, including HSP70, in small animal models suggests that HSPs may be involved in rescuing damaged cells in close proximity to the ablation zone and, therefore, limiting the therapeutic effects (8,9). In addition, HSPs have been identified to promote carcinogenesis by inhibiting apoptosis (10-14) and enhancing resistance to treatment (15,16). However, it has been established that HSPs function differently in different tumors (10,15).HSP27 is a 27-kDa protein that regulates apoptosis by interacting with key components of apoptotic signaling pathways, particularly those involved in the activation of caspases. Increasing evidence has indicated that HSP27 may play an important role in cancer (17). The expression of HSP27 has been associated with poor prognoses in ovarian (18), breast (10,19), gastric (20) and prostate cancers (21), as well as in osteoscarcomas (14). In addition, HSP27 has been reported to be associated with poor prognoses in patients with lung cancer (22). However, whether the expression of HSP27 has a prognostic role in lung cancer remains controversial. Zimmermann et al (22) reported that the level of serum HSP27 was positively correlated with advanced lung...

Heat Shock Protein 27, a Novel Regulator of Transforming Growth Factor β Induced Resistance to Cisplatin in A549 Cell

“…Among those genes, heat-shock protein 27 (HSP27), has been identified as an important regulator involved in the development of various cancers and chemoresistance during drug treatment [13,14,15]. HSP27 was highly expressed in mouse lung cancer tissues by the overexpression of HSP27 promoted cell proliferation via the activation of activator protein-1 signaling pathway [16]. In hepatocellular carcinoma (HCC), the patients with high expression of HSP27 displayed poor prognosis [15].…”

Distinct prognostic roles of HSPB1 expression in non-small cell lung cancer

“…Recent investigation indicated that the protein expression of HSPB1 was increased in the mouse lung tissue with lung cancer [7], and predicted the relationship between the expression of HSPB1 and lung cancer progression. In this study, we investigated the prognostic values of HSPB1 expression in NSCLC patients through analyzing the OS of NSCLC patients by using the KM plotter database.…”

“…And recent investigations in animal models and cell culture system also suggested that HSPB1 expression is associated with the tumor progression in various human cancers. Molecular biological investigations to study the expression of HSPB1 in tumor tissues and cells from human cancer patients have proved that the expression of HSPB1 is significantly higher in tumor tissues than control tissues from human hepatocellular carcinoma [6] and prostate cancer [4,8,32] and mouse lung cancer [7]. In human hepatocellular carcinoma, HSPB1 stimulates tumor progression through facilitating the hepatocellular carcinoma cells metastasis via Akt signaling [6,22].…”

“…Both in vivo and in vitro studies of the prostate cancer indicated that HSPB1 regulates human prostate cancer cell motility and metastatic progression via increased the expression of matrix metalloproteinase 2 (MMP-2) [29], which is a key stimulator for cancer cell invasion [33]. In mouse lung cancer development, HSPB1 was proved to induce the lung cancer cells proliferation via activator protein-1 (AP-1) dependent pathway [7]. Additionally, HSPB1 also plays critical roles to the initiation of the chemotherapeutic resistance in prostate cancer [8] and colon cancer [34], and this may through the lated to better OS in patients without chemotherapy HR 1.66 (1.16-2.36), p=0.0046 ( Figure 4B).…”

“…Accumulated evidences indicated that HSPB1 was involved in the pathogenesis of various cancers [4][5][6]. HSPB1 was highly expressed in mouse lung cancer tissues and stimulated cell proliferation through activator protein-1 (AP-1) related pathway [7]. In hepatocellular carcinoma (HCC) patients, the high expression of HSPB1 indicated poor prognosis [6].…”