Browse
Submit Data
Databases
API
Help

Dataset Information

9 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Heat shock protein A12A activates migration of hepatocellular carcinoma cells in a monocarboxylate transporter 4-dependent manner.

ABSTRACT: Metastasis is responsible for most of the hepatocellular carcinoma (HCC)-associated death. However, its underlying mechanism has yet to be fully elucidated. Glycolysis-derived lactate has been shown to be a powerful regulator of cancer metastasis. Heat shock protein A12A (HSPA12A) encodes a novel member of HSP70 family. We have recently demonstrated that heat shock protein A12A (HSPA12A) inhibited renal cancer cell migration by suppressing lactate output and glycolytic activity, which were mediated by unstabilizing CD147 and promoting its degradation. By striking contrast, here we demonstrated that HSPA12A promoted migration of human HCC cells. Extracellular acidification, lactate export, and glycolytic activity in HCC cells were also promoted following HSPA12A overexpression. Further analysis revealed that HSPA12A interacted with MCT4 and increased its membrane localization, thereby promoting export of lactate generated from glycolysis; this led, ultimately, to HCC cell migration. Our results revealed the opposite effect of HSPA12A on migration of renal cancer cells and that of HCC cells. Of note, in contrast to the inhibitory effect on CD147 expression in renal cancer cells, we found that HSPA12A increased CD147 expression in HCC cells, indicating that the expression of CD147 might exist heterogeneity in different cancer cell types. Taken together, we identified HSPA12A as an activator of HCC migration, a role opposite to that of renal cancer cells. Inhibiting HSPA12A might be a potential therapeutic intervention for HCC metastasis.

SUBMITTER: Min X

PROVIDER: S-EPMC8821763 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Oxidation of heat shock protein 60 and protein disulfide isomerase activates ERK and migration of human hepatocellular carcinoma HepG2.

Project description:Hepatocyte growth factor (HGF) and its receptor c-Met were frequently deregulated in hepatocellular carcinoma (HCC). Signaling pathways activated by HGF-c-Met are promising targets for preventing HCC progression. HGF can induce the reactive oxygen species (ROS) signaling for cell adhesion, migration and invasion of tumors including HCC. On the other hand, extracellular signal-regulated kinases (ERK), member of mitogen activated kinase, can be activated by ROS for a lot of cellular processes. As expected, HGF-induced phosphorylation of ERK and progression of HCC cell HepG2 were suppressed by ROS scavengers. By N-(biotinoyl)-N'-(iodoacetyl)-ethylenediamine (BIAM) labeling method, a lot of cysteine (-SH)-containing proteins with M.W. 50-75 kD were decreased in HepG2 treated with HGF or two other ROS generators, 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and phenazine methosulfate. These redox sensitive proteins were identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry. Among them, two chaperones, heat shock protein 60 (HSP60) and protein disulfide isomerase (PDI), were found to be the most common redox sensitive proteins in responding to all three agonists. Affinity blot of BIAM-labeled, immunoprecipitated HSP60 and PDI verified that HGF can decrease the cysteine (-SH) containing HSP60 and PDI. On the other hand, HGF and TPA increased cysteinyl glutathione-containing HSP60, consistent with the decrease of cysteine (-SH)-containing HSP60. Moreover, depletion of HSP60 and PDI or expression of dominant negative mutant of HSP60 with alteration of Cys, effectively prevented HGF-induced ERK phosphorylation and HepG2 migration.In conclusion, the redox sensitive HSP60 and PDI are required for HGF-induced ROS signaling and potential targets for preventing HCC progressions.

| S-EPMC4905458 | biostudies-literature

Evidence for Urate Uptake Through Monocarboxylate Transporter 9 Expressed in Mammalian Cells and Its Enhancement by Heat Shock.

Project description:Background: Monocarboxylate transporter 9 (MCT9), an orphan transporter member of the solute carrier family 16 (SLC16), possibly reabsorbs uric acid in the renal tubule and has been suggested by genome-wide association studies to be involved in the development of hyperuricemia and gout. In this study we investigated the mechanisms regulating the expression of human (h) MCT9, its degradation, and physiological functions. Methods?and?Results: hMCT9-FLAG was stably expressed in HEK293 cells and its degradation, intracellular localization, and urate uptake activities were assessed by pulse-chase analysis, immunofluorescence, and [14C]-urate uptake experiments, respectively. hMCT9-FLAG was localized on the plasma membrane as well as in the endoplasmic reticulum and Golgi apparatus. The proteasome inhibitors MG132 and lactacystine increased levels of hMCT9-FLAG protein expression with enhanced ubiquitination, prolonged their half-life, and decreased [14C]-urate uptake. [14C]-urate uptake was increased by both heat shock (HS) and the HS protein inducer geranylgeranylacetone (GGA). Both HS and GGA restored the [14C]-urate uptake impaired by MG132. Conclusions: hMCT9 does transport urate and is degraded by a proteasome, inhibition of which reduces hMCT9 expression on the cell membrane and urate uptake. HS enhanced urate uptake through hMCT9.

| S-EPMC7819574 | biostudies-literature

Heat Shock Protein 60 in Hepatocellular Carcinoma: Insights and Perspectives.

Project description:Heat shock protein 60 (HSP60) is a mitochondrial chaperone that is implicated in physiological and pathological processes. For instance, it contributes to protein folding and stability, translocation of mitochondrial proteins, and apoptosis. Variations in the expression levels of HSP60 have been correlated to various diseases and cancers, including hepatocellular carcinoma (HCC). Unlike other HSPs which clearly increase in some cancers, data about HSP60 levels in HCC are controversial and difficult to interpret. In the current review, we summarize and simplify the current knowledge about the role of HSP60 in HCC. In addition, we highlight the possibility of its targeting, using chemical compounds and/or genetic tools for treatment of HCC.

| S-EPMC7174549 | biostudies-literature

Crowding Activates Heat Shock Protein 90.

Project description:Hsp90 is a dimeric ATP-dependent chaperone involved in the folding, maturation, and activation of diverse target proteins. Extensive in vitro structural analysis has led to a working model of Hsp90's ATP-driven conformational cycle. An implicit assumption is that dilute experimental conditions do not significantly perturb Hsp90 structure and function. However, Hsp90 undergoes a dramatic open/closed conformational change, which raises the possibility that this assumption may not be valid for this chaperone. Indeed, here we show that the ATPase activity of Hsp90 is highly sensitive to molecular crowding, whereas the ATPase activities of Hsp60 and Hsp70 chaperones are insensitive to crowding conditions. Polymer crowders activate Hsp90 in a non-saturable manner, with increasing efficacy at increasing concentration. Crowders exhibit a non-linear relationship between their radius of gyration and the extent to which they activate Hsp90. This experimental relationship can be qualitatively recapitulated with simple structure-based volume calculations comparing open/closed configurations of Hsp90. Thermodynamic analysis indicates that crowding activation of Hsp90 is entropically driven, which is consistent with a model in which excluded volume provides a driving force that favors the closed active state of Hsp90. Multiple Hsp90 homologs are activated by crowders, with the endoplasmic reticulum-specific Hsp90, Grp94, exhibiting the highest sensitivity. Finally, we find that crowding activation works by a different mechanism than co-chaperone activation and that these mechanisms are independent. We hypothesize that Hsp90 has a higher intrinsic activity in the cell than in vitro.

| S-EPMC4813586 | biostudies-literature

14-3-3? induces heat shock protein 70 expression in hepatocellular carcinoma.

Project description:BACKGROUND: 14-3-3? is implicated in promoting tumor development of various malignancies. However, the clinical relevance of 14-3-3? in hepatocellular carcinoma (HCC) tumor progression and modulation and pathway elucidation remain unclear. METHODS: We investigated 14-3-3? expression in 109 HCC tissues by immunohistochemistry. Overexpression and knockdown experiments were performed by transfection with cDNA or siRNA. Protein expression and cell migration were determined by Western blot and Boyden chamber assay. RESULTS: In this study, we found that 14-3-3? is abundantly expressed in HCC tumors. Stable or transient overexpression of 14-3-3? induces the expression of heat shock factor-1? (HSF-1?) and heat shock protein 70 (HSP70) in HCC cells. Moreover, expression of 14-3-3? significantly correlates with HSF-1?/HSP70 in HCC tumors and both 14-3-3? and HSP70 overexpression are associated with micro-vascular thrombi in HCC patients, suggesting that 14-3-3?/HSP70 expression is potentially involved in cell migration/invasion. Results of an in vitro migration assay indicate that 14-3-3? promotes cell migration and that 14-3-3?-induced cell migration is impaired by siRNA knockdown of HSP70. Finally, 14-3-3?-induced HSF-1?/HSP70 expression is abolished by the knockdown of ?-catenin or activation of GSK-3?. CONCLUSIONS: Our findings indicate that 14-3-3? participates in promoting HCC cell migration and tumor development via ?-catenin/HSF-1?/HSP70 pathway regulation. Thus, 14-3-3? alone or combined with HSP70 are potential prognostic biomarkers for HCC.

| S-EPMC4061114 | biostudies-literature

Nonnative disulfide bond formation activates the ?32-dependent heat shock response in Escherichia coli.

Project description:Formation of nonnative disulfide bonds in the cytoplasm, so-called disulfide stress, is an integral component of oxidative stress. Quantification of the extent of disulfide bond formation in the cytoplasm of Escherichia coli revealed that disulfide stress is associated with oxidative stress caused by hydrogen peroxide, paraquat, and cadmium. To separate the impact of disulfide bond formation from unrelated effects of these oxidative stressors in subsequent experiments, we worked with two complementary approaches. We triggered disulfide stress either chemically by diamide treatment of cells or genetically in a mutant strain lacking the major disulfide-reducing systems TrxB and Gor. Studying the proteomic response of E. coli exposed to disulfide stress, we found that intracellular disulfide bond formation is a particularly strong inducer of the heat shock response. Real-time quantitative PCR experiments showed that disulfide stress induces the heat shock response in E. coli ?(32) dependently. However, unlike heat shock treatment, which induces these genes transiently, transcripts of ?(32)-dependent genes accumulated over time in disulfide stress-treated cells. Analyzing the stability of ?(32), we found that this constant induction can be attributed to an increase of the half-life of ?(32) upon disulfide stress. This is concomitant with aggregation of E. coli proteins treated with diamide. We conclude that oxidative stress triggers the heat shock response in E. coli ?(32) dependently. The component of oxidative stress responsible for the induction of heat shock genes is disulfide stress. Nonnative disulfide bond formation in the cytoplasm causes protein unfolding. This stabilizes ?(32) by preventing its DnaK- and FtsH-dependent degradation.

| S-EPMC3697257 | biostudies-literature

TTK activates Akt and promotes proliferation and migration of hepatocellular carcinoma cells.

Project description:Hepatocellular carcinoma (HCC) is one of the most malignant cancers with poor clinical outcome. The protein kinase human monopolar spindle 1 (hMps1/TTK) gene expression is significantly increased in HCCs. However, its contributions to hepatocarcinogenesis remain unclear. In this study, we found that TTK was overexpressed in 77.63% (118/152) HCC specimens. Elevated TTK expression positively correlated with large tumor size and presence of the portal vein tumor thrombus (PVTT). Demethylation in its promoter increased TTK expression in HCC. In vitro assays revealed that TTK not only promoted cell proliferation and anchorage-independent growth, but also cell migration. Subsequent investigations revealed that TTK activated Akt/mTOR pathway in a p53 dependent manner. We also found that TTK specific kinase inhibitor AZ3146 could decrease HCC cell growth. In conclusion, TTK contributes to HCC tumorigenesis via promoting cell proliferation and migration. It may serve as a novel biomarker and a potential target in HCC cancer therapy.

| S-EPMC4741454 | biostudies-literature

Monocarboxylate transporter 1 contributes to growth factor-induced tumor cell migration independent of transporter activity.

Project description:Tumor progression to metastatic disease contributes to the vast majority of incurable cancer. Understanding the processes leading to advanced stage cancer is important for the development of future therapeutic strategies. Here, we establish a connection between tumor cell migration, a prerequisite to metastasis, and monocarboxylate transporter 1 (MCT1). MCT1 transporter activity is known to regulate aspects of tumor progression and, as such, is a clinically relevant target for treating cancer. Knockdown of MCT1 expression caused decreased hepatocyte growth factor (HGF)-induced as well as epidermal growth factor (EGF)-induced tumor cell scattering and wound healing. Western blot analysis suggested that MCT1 knockdown (KD) hinders signaling through the HGF receptor (c-Met) but not the EGF receptor. Exogenous, membrane-permeable MCT1 substrates were not able to rescue motility in MCT1 KD cells, nor was pharmacologic inhibition of MCT1 able to recapitulate decreased cell motility as seen with MCT1 KD cells, indicating transporter activity of MCT1 was dispensable for EGF- and HGF-induced motility. These results indicate MCT1 expression, independent of transporter activity, is required for growth factor-induced tumor cell motility. The findings presented herein suggest a novel function for MCT1 in tumor progression independent of its role as a monocarboxylate transporter.

| S-EPMC5078044 | biostudies-literature

Heat stress activates YAP/TAZ to induce the heat shock transcriptome.

Project description:The Hippo pathway plays critical roles in cell growth, differentiation, organ development and tissue homeostasis, whereas its dysregulation can lead to tumorigenesis. YAP and TAZ are transcription co-activators and represent the main downstream effectors of the Hippo pathway. Here, we show that heat stress induces a strong and rapid YAP dephosphorylation and activation. The effect of heat shock on YAP is dominant to other signals known to modulate the Hippo pathway. Heat shock inhibits LATS kinase by promoting HSP90-dependent LATS interaction with and inactivation by protein phosphatase 5. Heat shock also induces LATS ubiquitination and degradation. YAP and TAZ are crucial for cellular heat shock responses, including the heat shock transcriptome and cell viability. This study uncovers previously unknown mechanisms of Hippo regulation by heat shock, as well as physiological functions of YAP, in the heat stress response. Our observations also reveal a potential combinational therapy involving hyperthermia and targeting of the Hippo pathway.

| S-EPMC7757600 | biostudies-literature

p16 Stimulates CDC42-dependent migration of hepatocellular carcinoma cells.

Project description:Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Tumor dissemination to the extra-hepatic region of the portal vein, lymph nodes, lungs or bones contributes to the high mortality seen in HCC; yet, the molecular mechanisms responsible for HCC metastasis remain unclear. Prior studies have suggested a potential link between accumulated cytoplasm-localized p16 and tumor progression. Here we report that p16 enhances metastasis-associated phenotypes in HCC cells - ectopic p16 expression increased cell migration in vitro, and lung colonization after intravenous injection, whereas knockdown of endogenous p16 reduced cell migration. Interestingly, analysis of p16 mutants indicated that the Cdk4 interaction domain is required for stimulation of HCC cell migration; however, knockdown of Cdk4 and Cdk6 showed that these proteins are dispensable for this phenomenon. Intriguingly, we found that in p16-positive HCC samples, p16 protein is predominantly localized in the cytoplasm. In addition, we identified a potential role for nuclear-cytoplasmic shuttling in p16-stimulated migration, consistent with the predominantly cytoplasmic localization of p16 in IHC-positive HCC samples. Finally, we determined that p16-stimulated cell migration requires the Cdc42 GTPase. Our results demonstrate for the first time a pro-migratory role for p16, and suggest a potential mechanism for the observed association between cytoplasmic p16 and tumor progression in diverse tumor types.

| S-EPMC3722281 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data