Role of HSP60/HSP10 in Lung Cancer: Simple Biomarkers or Leading Actors?

Fucarino, Alberto; Pitruzzella, Alessandro

doi:10.1155/2020/4701868

Cited by 18 publications

(12 citation statements)

References 88 publications

(74 reference statements)

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“…HSPs play critical roles in inhibiting pro-apoptotic molecules through the modulation of several signaling cascades such as JNK, AKT, and NF-κB [44]. Several HSP members are closely associated with the onset and progression of several human cancer types [45][46][47][48][49], but the expression pattern and potential roles of HSPs in breast cancer, as well as their underlying regulatory mechanisms, remain poorly investigated. Only two recent studies investigated the prognostic significance of HSP members in BC, exclusively limited to the transcriptomic analysis [50,51].…”

Section: Discussionmentioning

confidence: 99%

Prognostic and Functional Significant of Heat Shock Proteins (HSPs) in Breast Cancer Unveiled by Multi-Omics Approaches

Buttacavoli

Cara

D’Amico

et al. 2021

Biology

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Heat shock proteins (HSPs) are a well-characterized molecular chaperones protein family, classified into six major families, according to their molecular size. A wide range of tumors have been shown to express atypical levels of one or more HSPs, suggesting that they could be used as biomarkers. However, the collective role and the possible coordination of HSP members, as well as the prognostic significance and the functional implications of their deregulated expression in breast cancer (BC) are poorly investigated. Here, we used a systematic multi-omics approach to assess the HSPs expression, the prognostic value, and the underlying mechanisms of tumorigenesis in BC. By using data mining, we showed that several HSPs were deregulated in BC and significantly correlated with a poor or good prognosis. Functional network analysis of HSPs co-expressed genes and miRNAs highlighted their regulatory effects on several biological pathways involved in cancer progression. In particular, these pathways concerned cell cycle and DNA replication for the HSPs co-expressed genes, and miRNAs up-regulated in poor prognosis and Epithelial to Mesenchymal Transition (ETM), as well as receptors-mediated signaling for the HSPs co-expressed genes up-regulated in good prognosis. Furthermore, the proteomic expression of HSPs in a large sample-set of breast cancer tissues revealed much more complexity in their roles in BC and showed that their expression is quite variable among patients and confined into different cellular compartments. In conclusion, integrative analysis of multi-omics data revealed the distinct impact of several HSPs members in BC progression and indicate that collectively they could be useful as biomarkers and therapeutic targets for BC management.

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Section: Discussionmentioning

confidence: 99%

Prognostic and Functional Significant of Heat Shock Proteins (HSPs) in Breast Cancer Unveiled by Multi-Omics Approaches

Buttacavoli

Cara

D’Amico

et al. 2021

Biology

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“…HSPs can be highly expressed in cancer cells, where they promote cell proliferation, metastasis and drug resistance. HSPD1 is an ATP-dependent HSP mainly localized in the mitochondria, playing an essential role in guaranteeing the correct folding of the mitochondrial-imported proteins [ 44 ] and some data are available on its role as a stemness/metastasis regulator in other cancers [ 22 , 45 , 46 ]. In lung cancer, HSPD1 has been previously found highly expressed in NSCLC tissues [ 47 ] and identified as a predictive marker for survival in both smokers and non-smokers patients [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, HSPD1 carries a central role in cancer development, with either pro-survival or pro-apoptotic functions reported in different tumor types [ 20 ]. In NSCLC, HSPD1 has been proposed as a biomarker, but little is known about its role or the effects of its suppression [ 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Metabolic impairment of non-small cell lung cancers by mitochondrial HSPD1 targeting

Parma

Ramesh

Gollavilli

et al. 2021

J Exp Clin Cancer Res

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Background The identification of novel targets is of paramount importance to develop more effective drugs and improve the treatment of non-small cell lung cancer (NSCLC), the leading cause of cancer-related deaths worldwide. Since cells alter their metabolic rewiring during tumorigenesis and along cancer progression, targeting key metabolic players and metabolism-associated proteins represents a valuable approach with a high therapeutic potential. Metabolic fitness relies on the functionality of heat shock proteins (HSPs), molecular chaperones that facilitate the correct folding of metabolism enzymes and their assembly in macromolecular structures. Methods Gene fitness was determined by bioinformatics analysis from available datasets from genetic screenings. HSPD1 expression was evaluated by immunohistochemistry from formalin-fixed paraffin-embedded tissues from NSCLC patients. Real-time proliferation assays with and without cytotoxicity reagents, colony formation assays and cell cycle analyses were used to monitor growth and drug sensitivity of different NSCLC cells in vitro. In vivo growth was monitored with subcutaneous injections in immune-deficient mice. Cell metabolic activity was analyzed through extracellular metabolic flux analysis. Specific knockouts were introduced by CRISPR/Cas9. Results We show heat shock protein family D member 1 (HSPD1 or HSP60) as a survival gene ubiquitously expressed in NSCLC and associated with poor patients’ prognosis. HSPD1 knockdown or its chemical disruption by the small molecule KHS101 induces a drastic breakdown of oxidative phosphorylation, and suppresses cell proliferation both in vitro and in vivo. By combining drug profiling with transcriptomics and through a whole-genome CRISPR/Cas9 screen, we demonstrate that HSPD1-targeted anti-cancer effects are dependent on oxidative phosphorylation and validated molecular determinants of KHS101 sensitivity, in particular, the creatine-transporter SLC6A8 and the subunit of the cytochrome c oxidase complex COX5B. Conclusions These results highlight mitochondrial metabolism as an attractive target and HSPD1 as a potential theranostic marker for developing therapies to combat NSCLC.

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“…Our results suggested that ectopic expression HNF1A promoted radio-resistance of ESCC to release potential oncogenic ability. HSPD1 had been identi ed as a high-quality prognostic biomarker in multiple cancers, such as non-small cell lung cancer, ovarian cancer, metastatic colorectal cancer, gastric cancer, hepatocellular carcinoma (14)(15)(16)(17)(18)(19)(20)(21). At the same time, HSPD1 inhibitors and antibodies had shown remarkable e cacy in basic experiments (22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

Exosome Releasing HSPD1 Assists HNF1A in Regulating the Invasion Ability and Radiosensitivity of Esophageal Squamous Cell Carcinoma Cells via Activating EMT

Zou¹,

Jing²,

Zhang³

et al. 2021

Preprint

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Background: Concurrent chemoradiotherapy is the standard scheme for locally advanced non-surgical esophageal squamous cell carcinoma (ESCC). But there are frequently different results due to tumor heterogeneity. HNF1A and HSPD1 have been shown to be associated with the invasion, proliferation, apoptosis, and chemical resistance in multiple cancers. The aim of this study was to investigate the effects of HNF1A and HSPD1 on invasion and radiosensitivity of ESCC.Methods: HNF1A was overexpressed by lentivirus transfection and HSPD1 was silenced by knockdown plasmid in TE1 and KYSE150 cells. The mRNA expression of HSPD1 and HNF1A were detected by RT-qPCR. The correlated proteins expression was verified by western blot, and transwell tested the invasion ability of ESCC cells. Survival curve was plotted by colony formation assay. Co-immunoprecipitation and immunofluorescence assays were used to detect interaction and subcellular location of HNF1A and HSPD1. At the same time, we explored the change of HSPD1 protein in exosomes by western blotting.Results: Immunoprecipitation and mass spectrometry identified the combination of HNF1A and HSPD1/hnRNPA1/A3/TCP1 in TE1 cells. Co-immunoprecipitation and immunofluorescence experiments were verified the bind of HNF1A and HSPD1 again, but HNF1A did not regulate HSPD1 expression. Subsequently, HSPD1 knockout reversed HNF1A to promote invasion ability of cells by inhibiting EMT. Likewise, deletion of HSPD1 relieved radio-resistance from overexpression of HNF1A in TE1 and KYSE150 cells. Notably, induced cells to release abundant of HSPD1 through exosome, and ectopic expression of HNF1A prevented radiation-induced exosomal releasing of HSPD1.Conclusions: We initially demonstrated that HNF1A was assisted by HSPD1 to drive EMT process and promote invasion of ESCC cells, and explained that HNF1A prevented HSPD1 from releasing to extracellular with exosomes after irradiation, thereby causing radio-resistance. These findings provided theoretical basis of gene target treatment for radiotherapy of ESCC.

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Role of HSP60/HSP10 in Lung Cancer: Simple Biomarkers or Leading Actors?

Cited by 18 publications

References 88 publications

Prognostic and Functional Significant of Heat Shock Proteins (HSPs) in Breast Cancer Unveiled by Multi-Omics Approaches

Prognostic and Functional Significant of Heat Shock Proteins (HSPs) in Breast Cancer Unveiled by Multi-Omics Approaches

Metabolic impairment of non-small cell lung cancers by mitochondrial HSPD1 targeting

Exosome Releasing HSPD1 Assists HNF1A in Regulating the Invasion Ability and Radiosensitivity of Esophageal Squamous Cell Carcinoma Cells via Activating EMT

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