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Decreased expression of heat shock protein 20 in colorectal cancer and its implication in tumorigenesis. Ju Young-Tae,Kwag Seung-Jin,Park Hee Jin,Jung Eun-Jung,Jeong Chi-Young,Jeong Sang-Ho,Lee Young-Joon,Choi Sang-Kyung,Kang Kee Ryeon,Hah Young-Sool,Hong Soon-Chan Journal of cellular biochemistry 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. 10.1002/jcb.24966
Heat shock protein 20 suppresses breast carcinogenesis by inhibiting the MAPK and AKT signaling pathways. Oncology letters Heat shock protein (HSP) 20 belongs to the small HSP family and exhibits diverse functions, including tumor suppression, in addition to being a molecular chaperon, which is the classical property of HSPs. The present study aimed to examine the association between HSP20 expression and breast cancer (BC) progression in patients, and to explore the possible role of HSP20 in malignant phenotypes of BC cells. A series of experiments, including reverse transcription-quantitative PCR, western blotting, Cell Counting Kit-8 and flow cytometry, were performed. Data from Gene Expression Omnibus and Kaplan-Meier Plotter revealed that HSP20 expression was significantly downregulated in BC tissues, and patients with BC with lower HSP20 expression exhibited poorer recurrence-free survival. The data revealed that HSP20 was closely associated with the pathological tumor stage (P=0.015) and pathological tumor node metastasis (P=0.031) of patients with BC. Additionally, HSP20 expression was markedly decreased in BC cell lines. Exogenous overexpression of HSP20 inhibited proliferation and accelerated apoptosis of BC cells. These cells exhibited decreased migration and invasion when HSP20 was overexpressed. Furthermore, HSP20 overexpression suppressed the MAPK and AKT signaling pathways, as evidenced by the reduced phosphorylation levels of AKT, ERK, JNK and p38. Knockdown of HSP20 exerted the opposite effects. Notably, the AKT agonist, SC79, and the ERK agonist, LM22B-10, reversed the decrease in cell proliferation and migration induced by HSP20 overexpression. Overall, the data suggest that the decreased expression of HSP20 in BC tissues may be associated with disease progression. HSP20 also attenuated the malignant phenotype of BC cells and the inhibition of MAPK and AKT signaling may be associated with this effect. Therefore, HSP20 may be a potential prognostic marker or a candidate therapeutic target for BC. 10.3892/ol.2022.13582
The role and therapeutic potential of heat shock proteins in haemorrhagic stroke. Shao Anwen,Zhou Yunxiang,Yao Yihan,Zhang Wenhua,Zhang Jianmin,Deng Yongchuan Journal of cellular and molecular medicine Heat shock proteins (HSPs) are induced after haemorrhagic stroke, which includes subarachnoid haemorrhage (SAH) and intracerebral haemorrhage (ICH). Most of these proteins function as neuroprotective molecules to protect cerebral neurons from haemorrhagic stroke and as markers to indicate cellular stress or damage. The most widely studied HSPs in SAH are HSP70, haeme oxygenase-1 (HO-1), HSP20 and HSP27. The subsequent pathophysiological changes following SAH can be divided into two stages: early brain injury and delayed cerebral ischaemia, both of which determine the outcome for patients. Because the mechanisms of HSPs in SAH are being revealed and experimental models in animals are continually maturing, new agents targeting HSPs with limited side effects have been suggested to provide therapeutic potential. For instance, some pharmaceutical agents can block neuronal apoptosis signals or dilate cerebral vessels by modulating HSPs. HO-1 and HSP70 are also critical topics for ICH research, which can be attributed to their involvement in pathophysiological mechanisms and therapeutic potential. However, the process of HO-1 metabolism can be toxic owing to iron overload and the activation of succedent pathways, for example, the Fenton reaction and oxidative damage; the overall effect of HO-1 in SAH and ICH tends to be protective and harmful, respectively, given the different pathophysiological changes in these two types of haemorrhagic stroke. In the present study, we focus on the current understanding of the role and therapeutic potential of HSPs involved in haemorrhagic stroke. Therefore, HSPs may be potential therapeutic targets, and new agents targeting HSPs are warranted. 10.1111/jcmm.14479
Novel cardioprotective role of a small heat-shock protein, Hsp20, against ischemia/reperfusion injury. Fan Guo-Chang,Ren Xiaoping,Qian Jiang,Yuan Qunying,Nicolaou Persoulla,Wang Yang,Jones W Keith,Chu Guoxiang,Kranias Evangelia G Circulation BACKGROUND:Heat-shock proteins (Hsps) have been shown to render cardioprotection from stress-induced injury; however, little is known about the role of another small heat-shock protein, Hsp20, which regulates activities of vasodilation and platelet aggregation, in cardioprotection against ischemia injury. We recently reported that increased expression of Hsp20 in cardiomyocytes was associated with improved contraction and protection against beta-agonist-induced apoptosis. METHODS AND RESULTS:To investigate whether overexpression of Hsp20 exerts protective effects in both ex vivo and in vivo ischemia/reperfusion (I/R) injury, we generated a transgenic (TG) mouse model with cardiac-specific overexpression of Hsp20 (10-fold). TG and wild-type (WT) hearts were then subjected to global no-flow I/R (45 minutes/120 minutes) using the Langendorff preparation. TG hearts exhibited improved recovery of contractile performance over the whole reperfusion period. This improvement was accompanied by a 2-fold decrease in lactate dehydrogenase released from the TG hearts. The extent of infarction and apoptotic cell death was also significantly decreased, which was associated with increased protein ratio of Bcl-2/Bax and reduced caspase-3 activity in TG hearts. Furthermore, in vivo experiments of 30-minute myocardial ischemia, via coronary artery occlusion, followed by 24-hour reperfusion, showed that the infarct region-to-risk region ratio was 8.1+/-1.1% in TG hearts (n=7), compared with 19.5+/-2.1% in WT hearts (n=11, P<0.001). CONCLUSIONS:Our data demonstrate that increased Hsp20 expression in the heart protects against I/R injury, resulting in improved recovery of cardiac function and reduced infarction. Thus, Hsp20 may constitute a new therapeutic target for ischemic heart diseases. 10.1161/01.CIR.0000160851.41872.C6
The cardioprotective role of small heat-shock protein 20. Martin Tamara P,Currie Susan,Baillie George S Biochemical Society transactions The small HSP (heat-shock protein) HSP20 is a molecular chaperone that is transiently up-regulated in response to cellular stress/damage. Although ubiquitously expressed in various tissues, it is most highly expressed in skeletal, cardiac and smooth muscle. Phosphorylation at Ser16 by PKA (cAMP-dependent protein kinase) is essential for HSP20 to confer its protective qualities. HSP20 and its phosphorylation have been implicated in a variety of pathophysiological processes, but most prominently cardiovascular disease. A wealth of knowledge of the importance of HSP20 in contractile function and cardioprotection has been gained over the last decade. The present mini-review highlights more recent findings illustrating the cardioprotective properties of HSP20 and its potential as a therapeutic agent. 10.1042/BST20130272
Hsp20 Protects against Oxygen-Glucose Deprivation/Reperfusion-Induced Golgi Fragmentation and Apoptosis through Fas/FasL Pathway. Zhong Bingwu,Hu Zhiping,Tan Jieqiong,Lu Tonglin,Lei Qiang,Chen Chunli,Zeng Liuwang Oxidative medicine and cellular longevity Cerebral ischemia-reperfusion injury plays an important role in the development of tissue injury after acute ischemic stroke. Finding effective neuroprotective agents has become a priority in the treatment of ischemic stroke. The Golgi apparatus (GA) is a pivotal organelle and its protection is an attractive target in the treatment of cerebral ischemia-reperfusion injury. Protective effects of Hsp20, a potential cytoprotective agent due to its chaperone-like activity and involvement in regulation of many vital processes, on GA were assessed in an ischemia-reperfusion injury model. Mouse neuroblastoma Neuro2a (N2a) cells were subjected to oxygen-glucose deprivation/reperfusion (OGDR) insult. OGDR induces Golgi fragmentation, apoptosis, and p115 cleavage in N2a cells. However, transfection with Hsp20 significantly attenuates OGDR-induced Golgi fragmentation and apoptosis. Hsp20 interacts with Bax, decreases FasL and Bax expression, and inhibits caspases 3 and p115 cleavage in N2a cells exposed to OGDR. Our data demonstrate that increased Hsp20 expression protects against OGDR-induced Golgi fragmentation and apoptosis, likely through interaction with Bax and subsequent amelioration of the OGDR-induced elevation in p115 cleavage via the Fas/FasL signaling pathway. This neuroprotective potential of Hsp20 against OGDR insult and the underlying mechanism will pave the way for its potential clinical application for cerebral ischemia-reperfusion related disorders. 10.1155/2015/606934
HSP20 Exerts a Protective Effect on Preeclampsia by Regulating Function of Trophoblast Cells Via Akt Pathways. Li Fanfan,Xie Yin,Wu Yuanyuan,He Mengzhou,Yang Meitao,Fan Yao,Li Xuanxuan,Qiao Fuyuan,Deng Dongrui Reproductive sciences (Thousand Oaks, Calif.) Preeclampsia (PE) remains the leading cause of maternal and fetal morbidity and mortality. Excessive apoptosis of the placenta and poor remodeling of spiral arteries caused by insufficient invasion of trophoblast cells into uterus have been implicated in the pathogenesis of PE. Accumulating evidence showed that heat shock protein 20 (HSP20) is closely associated with the proliferation, apoptosis, and metastasis of tumor cells. However, little is known about whether HSP20 plays a role in the development of PE. In this study, we detected the apoptosis index and the expressions of HSP20 and apoptosis-associated proteins in the placentas from PE and normal pregnancies. We found that HSP20 was reversely related to the apoptosis rate and the levels of proapoptotic proteins. Moreover, we identified that HSP20 could suppress the proliferation and apoptosis of trophoblast cells, turning them into a more invasive phenotype. Additionally, HO-induced oxidative stress was significantly alleviated, and several key proteins on the Akt signaling pathway were upregulated in HSP20-overexpressing trophoblast cells. These findings strongly suggested that HSP20 might play a role in the remodeling of spiral arteries through affecting the invasiveness of extravillous trophoblast cells via Akt signaling pathway, and the dysregulation of it might contribute to the pathophysiology of PE. 10.1177/1933719118802057
Phosphorylation of Hsp20 Promotes Fibrotic Remodeling and Heart Failure. Gardner George T,Travers Joshua G,Qian Jiang,Liu Guan-Sheng,Haghighi Kobra,Robbins Nathan,Jiang Min,Li Yutian,Fan Guo-Chang,Rubinstein Jack,Blaxall Burns C,Kranias Evangelia G JACC. Basic to translational science Cardiomyocyte-specific increases in phosphorylated Hsp20 (S16D-Hsp20) to levels similar to those observed in human failing hearts are associated with early fibrotic remodeling and depressed left ventricular function, symptoms which progress to heart failure and early death. The underlying mechanisms appear to involve translocation of phosphorylated Hsp20 to the nucleus and upregulation of interleukin (IL)-6, which subsequently activates cardiac fibroblasts in a paracrine fashion through transcription factor STAT3 signaling. Accordingly, treatment of S16D-Hsp20 mice with a rat anti-mouse IL-6 receptor monoclonal antibody (MR16-1) attenuated interstitial fibrosis and preserved cardiac function. These findings suggest that phosphorylated Hsp20 may be a potential therapeutic target in heart failure. 10.1016/j.jacbts.2018.11.007
The BAG3-dependent and -independent roles of cardiac small heat shock proteins. Fang Xi,Bogomolovas Julius,Trexler Christa,Chen Ju JCI insight Small heat shock proteins (sHSPs) comprise an important protein family that is ubiquitously expressed, is highly conserved among species, and has emerged as a critical regulator of protein folding. While these proteins are functionally important for a variety of tissues, an emerging field of cardiovascular research reveals sHSPs are also extremely important for maintaining normal cardiac function and regulating the cardiac stress response. Notably, numerous mutations in genes encoding sHSPs have been associated with multiple cardiac diseases. sHSPs (HSPB5, HSPB6, and HSPB8) have been described as mediating chaperone functions within the heart by interacting with the cochaperone protein BCL-2-associated anthanogene 3 (BAG3); however, recent reports indicate that sHSPs (HSPB7) can perform other BAG3-independent functions. Here, we summarize the cardiac functions of sHSPs and present the notion that cardiac sHSPs function via BAG3-dependent or -independent pathways. 10.1172/jci.insight.126464
Overexpression of HSPB6 inhibits osteosarcoma progress through the ERK signaling pathway. Clinical and experimental medicine Heat shock protein B6 (HSPB6) plays a certain role in the formation of several cancers, whereas its effect on osteosarcoma remains unclear. In this study, the effect of HSPB6 on osteosarcoma was validated through numerous experiments. HSPB6 was down-regulated in osteosarcoma. As indicated by the result of CCK-8 and colony formation assays, HSPB6 overexpression was likely to inhibit the osteosarcoma cells proliferation, whereas the flow cytometry analysis suggested that apoptosis of osteosarcoma cells was increased after HSPB6 overexpression. Furthermore, transwell and wound healing assays suggested that when HSPB6 was overexpressed, osteosarcoma cells migration and invasion were declined. Moreover, the western blotting assay suggested that the protein level of p-ERK1/2 was down-regulated in osteosarcoma when HSPB6 was overexpressed. Besides, the effect of HSPB6 on osteosarcoma in vivo was examined. As indicated by the result, HSPB6 overexpression was likely to prevent osteosarcoma growth and lung metastasis in vivo. As revealed by the findings of this study, HSPB6 overexpression exerted anticancer effects in osteosarcoma through the ERK signaling pathway and HSPB6 may be suitable target for osteosarcoma molecular therapies. 10.1007/s10238-023-01216-9
Cellular functions of heat shock protein 20 (HSPB6) in cancer: A review. Cellular signalling Heat shock proteins (HSP) are a large family of peptide proteins that are widely found in cells. Studies have shown that the expression and function of HSPs in cells are very complex, and they can participate in cellular physiological and pathological processes through multiple pathways. Multiple heat shock proteins are associated with cancer cell growth, proliferation, metastasis, and resistance to anticancer drugs, and they play a key role in cancer development by ensuring the correct folding or degradation of proteins in cancer cells. As research hotspots, HSP90, HSP70 and HSP27 have been extensively studied in cancer so far. However, HSP20, also referred to as HSPB6, as a member of the small heat shock protein family, has been shown to play an important role in the cardiovascular system, but little research has been conducted on HSP20 in cancer. This review summarizes the current cellular functions of HSP20 in different cancer types, as well as its effects on cancer proliferation, progression, prognosis, and its other functions in cancer, to illustrate the close association between HSP20 and cancer. We show that, unlike most HSPs, HSP20 mainly plays an active anticancer role in cancer development, which is expected to provide new ideas and help for cancer diagnosis and treatment and research. 10.1016/j.cellsig.2023.110928
HSPB6 Deficiency Promotes the Development of Aortic Dissection and Rupture. Laboratory investigation; a journal of technical methods and pathology To better understand the pathogenesis of acute type A aortic dissection, high-sensitivity liquid chromatography-tandem mass spectrometry/mass spectrometry (LC-MS/MS)-based proteomics and phosphoproteomics approaches were used to identify differential proteins. Heat shock protein family B (small) member 6 (HSPB6) in aortic dissection was significantly reduced in human and mouse aortic dissection samples by real-time PCR, western blotting, and immunohistochemical staining techniques. Using an HSPB6-knockout mouse, we investigated the potential role of HSPB6 in β-aminopropionitrile monofumarate-induced aortic dissection. We found increased mortality and increased probability of ascending aortic dissection after HSPB6 knockout compared with wild-type mice. Mechanistically, our data suggest that HSPB6 deletion promoted vascular smooth muscle cell apoptosis. More importantly, HSPB6 deletion attenuated cofilin activity, leading to excessive smooth muscle cell stiffness and eventually resulting in the development of aortic dissection and rupture. Our data suggest that excessive stiffness of vascular smooth muscle cells caused by HSPB6 deficiency is a new pathogenetic mechanism leading to aortic dissection. 10.1016/j.labinv.2024.100326
An Hsp20-FBXO4 Axis Regulates Adipocyte Function through Modulating PPARγ Ubiquitination. Peng Jiangtong,Li Yutian,Wang Xiaohong,Deng Shan,Holland Jenna,Yates Emily,Chen Jing,Gu Haitao,Essandoh Kobina,Mu Xingjiang,Wang Boyu,McNamara Robert K,Peng Tianqing,Jegga Anil G,Liu Tiemin,Nakamura Takahisa,Huang Kai,Perez-Tilve Diego,Fan Guo-Chang Cell reports Exposure to cold temperature is well known to upregulate heat shock protein (Hsp) expression and recruit and/or activate brown adipose tissue and beige adipocytes in humans and animals. However, whether and how Hsps regulate adipocyte function for energy homeostatic responses is poorly understood. Here, we demonstrate a critical role of Hsp20 as a negative regulator of adipocyte function. Deletion of Hsp20 enhances non-shivering thermogenesis and suppresses inflammatory responses, leading to improvement of glucose and lipid metabolism under both chow diet and high-fat diet conditions. Mechanistically, Hsp20 controls adipocyte function by interacting with the subunit of the ubiquitin ligase complex, F-box only protein 4 (FBXO4), and regulating the ubiquitin-dependent degradation of peroxisome proliferation activated receptor gamma (PPARγ). Indeed, Hsp20 deficiency mimics and enhances the pharmacological effects of the PPARγ agonist rosiglitazone. Together, our findings suggest a role of Hsp20 in mediating adipocyte function by linking β-adrenergic signaling to PPARγ activity. 10.1016/j.celrep.2018.05.065
Inhibition of HSP20 Ameliorates Steatotic Liver Disease by Stimulating ERK2-Dependent Autophagy. Diabetes HSP20 emerges as a novel regulator of autophagy in the heart. Nonetheless, the detailed function of HSP20 in the liver and its effect on autophagy remain unknown. Here, we observed that HSP20 expression is increased in liver tissues from mice and patients with metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease. Liver-specific downregulation of HSP20 mitigates hepatic steatosis and insulin resistance in obese mice, while upregulating HSP20 promotes lipid deposition and hepatocyte cell death. Mechanistically, liquid chromatography-tandem mass spectrometry revealed that HSP20 interacts with phosphorylated extracellular regulated protein kinase 2 (ERK2) and prevents its dephosphorylation by dual specificity phosphatase 6, leading to ERK2-mediated repression of autophagy and resulting in aggravated saturated fatty acid (SFA)-triggered hepatocyte death. Importantly, such adverse effects could be ameliorated by ERK inhibitor. Our data reveal a framework of how HSP20 increases susceptibility of SFA-induced liver injury through enhancing ERK2 phosphorylation, which represents a plausible therapeutic intervention to combat MASLD. ARTICLE HIGHLIGHTS: 10.2337/db23-0688