Upregulation of heat shock factor 1 transcription activity is associated with hepatocellular carcinoma progression

Li, Shulian; Ma, Wanli; Teng, Fei; Lou, Qiang; Zhang, Yaqin; Cui, Xiukun; Qin, Xiaoming; Zhang, Jun; Liu, Guangchao; Dong, Zheng; Ma, Yuanfang; Song, Zhengshun; Hu, Yanzhong

doi:10.3892/mmr.2014.2547

Cited by 29 publications

(21 citation statements)

References 40 publications

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“…In our previous study, we found that HSF1 promoted invasion and metastasis of HCC cells and was associated with a poor prognosis for HCC patients (31). Currently, more and more studies have confirmed the important role of HSF1 in tumor progression of HCC (32)(33)(34). Here, we have proven that HSF1 may bind to À1,287$À1,263 site before transcriptional start site of miR-487a and mediate its expression.…”

Section: Discussionmentioning

confidence: 51%

miRNA-487a Promotes Proliferation and Metastasis in Hepatocellular Carcinoma

Chang

Xiao

Xiong

et al. 2017

Clinical Cancer Research

103

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Hepatocellular carcinoma (HCC) harbors highly metastatic properties, accounting for postoperative recurrence and metastasis. However, the mechanisms for metastasis and recurrence remain incompletely clear. This study aimed to investigate the role of hsa-miR-487a (miR-487a) in promoting the proliferation and metastasis of HCC and to elucidate the underlying molecular mechanisms. 198 HCC samples were analyzed for association between miR-487a expression and patient clinicopathological features and prognosis. The roles of miR-487a in proliferation and metastasis were validated both and The upstream regulator and downstream targets of miR-487a were determined using a dual luciferase reporter assay, chromatin immunoprecipitation and immunohistochemistry. Our results demonstrate that upregulated miR-487a correlates with a poor prognosis for HCC patients. miR-487a enhances proliferation and metastasis of HCC cells by directly binding to sprouty-related EVH1 domain containing 2 (SPRED2) or phosphoinositide-3-Kinase regulatory subunit 1 (PIK3R1). Interestingly, miR-487a mainly promotes metastasis via SPRED2 induced mitogen activated protein kinase signaling and promotes proliferation via PIK3R1 mediated AKT signaling. Transcription of miR-487a was found to be activated by up-regulated heat shock factor 1, which we previously demonstrated to be an important metastasis-associated transcription factor in a previous study. Phosphorodiamidate morpholino oligomers effectively silenced miR-487a and inhibited HCC tumor progression in mouse models. Our findings show that miR-487a, mediated by heat shock factor 1, promotes proliferation and metastasis of HCC by PIK3R1 and SPRED2 binding, respectively. Our study provides a rationale for developing miR-487a as a potential prognostic marker or a potential therapeutic target against HCC. .

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Section: Discussionmentioning

confidence: 51%

miRNA-487a Promotes Proliferation and Metastasis in Hepatocellular Carcinoma

Chang

Xiao

Xiong

et al. 2017

Clinical Cancer Research

103

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“…Under physiological conditions, HSF1 protects organisms and cells from various types of stress, such as heat, ischemia, oxidative stress, and other noxious conditions (Vihervaara and Sistonen, 2014). Several studies have demonstrated that HSF1 is activated and predicts a poor prognosis in various types of cancer, including breast cancer (Santagata et al, 2011), colon cancer (Jacobs and Marnett, 2009), and liver cancer (Li et al, 2014b). In cancer cells, HSF1 could drive a transcriptional program that is vital for supporting the malignant state of cancer, and the transcriptional program was highly enriched in protein translation, RNA binding, metabolism, and cell adhesion (Mendillo et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Loss of AMPK activation promotes the invasion and metastasis of pancreatic cancer through an HSF1‐dependent pathway

Chen

Qian

et al. 2017

Molecular Oncology

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Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a mortality rate that closely parallels its incidence rate, and a better understanding of the molecular and cellular mechanisms associated with the invasion and distant metastasis is required. Heat shock factor 1 (HSF1) is a very highly conserved factor in eukaryotes that regulates the protective heat shock response. Here, we show that HSF1 is abnormally activated in pancreatic cancer. The knockdown of HSF1 impaired the invasion and migration and epithelial–mesenchymal transition (EMT) of pancreatic cancer cells in vitro; however, the upregulation of HSF1 showed the opposite effects. In vivo, the pharmacological inhibition of HSF1 significantly reduced the tumor burden, decreased the incidence of invasion, and prolonged the overall survival of transgenic mice harboring the spontaneous pancreatic cancer. We suggest that the loss of AMP‐activated protein kinase (AMPK) activation mediates the abnormal activation of HSF1 based on the findings that phospho‐HSF1 (p‐HSF1) was highly expressed in human PDAC tissues with a low expression of p‐AMPK and that in those tissues with a high p‐AMPK expression, the level of p‐HSF1 was decreased. The in vivo and in vitro activation of AMPK impaired the activity of HSF1, and HSF1 mediated the effects of the AMPK knockdown‐induced pancreatic cancer invasion and migration. Our study revealed a novel mechanism by which the loss of AMPK activation amplifies the activity of HSF1 to promote the invasion and metastasis of pancreatic cancer.

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“…HSF1 facilitates survival in response stressors by regulating various cellular processes, such as cell-cycle control, protein translation and glucose metabolism (6,7). The expression of HSF1 is reportedly upregulated in cancer cell lines and cancer tissues of hepatocellular carcinoma, and high expression of HSF1 is associated with a poor prognosis in breast cancer and hepatocellular carcinoma (8,9). However, the role of HSF1 as a prognostic biomarker in ESCC has not been well investigated.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of heat-shock factor 1 is associated with a poor prognosis in esophageal squamous cell carcinoma

et al. 2017

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Abstract. Heat-shock factor 1 (HSF1) is the primary regulator of the response to various stressors. A previous study showed that HSF1 expression is associated with a poor prognosis in breast cancer and hepatocellular carcinoma; however, the prognostic significance of HSF1 in esophageal squamous cell carcinoma (ESCC) is unknown. Therefore, the present study investigated the association between HSF1 expression and the clinicopathological parameters of patients, as well as the association between HSF1 expression, and heat shock protein (Hsp)27, Hsp70 and Hsp90 expression induced by HSF1, by cDNA microarray and immunohistochemistry analyses. HSF1 protein and mRNA expression were assessed in resected specimens from 270 patients with ESCC in two independent cohorts. Hsp27, Hsp70 and Hsp90 expression were also assessed in 55/270 patients. Patients with high HSF1 expression had a significantly worse OS than those with low HSF1 expression in both cohorts. In multivariate analyses, pathological T stage [hazard ratio (HR), 2.21; 95% confidence interval (CI), 1.38-3.65; P=0.0008], pathological N stage (HR, 1.73; 95% CI, 1.04-3.02; P=0.03) and HSF1 expression (HR, 2.29; 95% CI, 1.48-3.64; P=0.0002) were statistically significant independent prognostic factors. Furthermore, Hsp27 and Hsp90 expression were significantly correlated with HSF1 expression (P<0.0001), but Hsp70 expression was not (P=0.38). These results indicate that HSF1 is a prognostic factor for patients with ESCC, and that Hsp27 and Hsp90, but not Hsp70, may be the downstream targets of HSF1 in ESCC.

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Upregulation of heat shock factor 1 transcription activity is associated with hepatocellular carcinoma progression

Cited by 29 publications

References 40 publications

miRNA-487a Promotes Proliferation and Metastasis in Hepatocellular Carcinoma

miRNA-487a Promotes Proliferation and Metastasis in Hepatocellular Carcinoma

Loss of AMPK activation promotes the invasion and metastasis of pancreatic cancer through an HSF1‐dependent pathway

Overexpression of heat-shock factor 1 is associated with a poor prognosis in esophageal squamous cell carcinoma

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