Gene Summary

Gene:PIAS3; protein inhibitor of activated STAT 3
Aliases: ZMIZ5
Summary:This gene encodes a member of the PIAS [protein inhibitor of activated STAT (signal transducer and activator of transcription)] family of transcriptional modulators. The protein functions as a SUMO (small ubiquitin-like modifier)-E3 ligase which catalyzes the covalent attachment of a SUMO protein to specific target substrates. It directly binds to several transcription factors and either blocks or enhances their activity. Alternatively spliced transcript variants of this gene have been identified, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:E3 SUMO-protein ligase PIAS3
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
Show (19)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: PIAS3 (cancer-related)

He T, McColl K, Sakre N, et al.
Post-transcriptional regulation of PIAS3 expression by miR-18a in malignant mesothelioma.
Mol Oncol. 2018; 12(12):2124-2135 [PubMed] Free Access to Full Article Related Publications
Protein inhibitor of activated STAT3 (PIAS3) is an endogenous suppressor of signal transducer and activator of transcription 3 (STAT3) signaling. By directly interacting with phosphorylated STAT3, PIAS3 can block the downstream transcriptional activity of STAT3, which is hyper-activated in various cancers. We previously reported that in malignant mesothelioma (MM), low PIAS3 expression is associated with increased STAT3 activation and correlates with poor patient survival, yet the regulatory mechanism(s) governing PIAS3 expression in MM remain unclear. Here, we demonstrate that PIAS3 protein expression does not correlate with its mRNA level in MM cell lines, indicating that PIAS3 expression is regulated at a post-transcriptional level. Inhibition of proteasomal degradation with MG132 (10 μm) or bortezomib (1 μm), alone and in combination, did not increase PIAS3 protein levels; furthermore, inhibition of protein synthesis by cycloheximide treatment did not decrease PIAS3 levels within 48 h, suggesting that PIAS3 expression is not actively regulated at a post-translational level. To determine whether miRNA (miRs) can translationally regulate PIAS3 expression, we combined miR microarray analysis with bioinformatic screening to identify candidate miRs, in MM cell lines with low PIAS3 expression, followed by luciferase reporter assays to validate miR regulation of the PIAS3 3'UTR. We identified miR-18a as a suppressor of PIAS3 expression that is upregulated in MM cells and whose inhibition can increase PIAS3 expression and suppress STAT3 activity. Moreover, we showed that miR-18a inhibition can decrease MM cell viability and that its expression is negatively correlated with MM patient survival. Taken together, these results suggest that targeting miR-18a may have therapeutic benefit in MM.

Song X, Shu XH, Wu ML, et al.
Postoperative resveratrol administration improves prognosis of rat orthotopic glioblastomas.
BMC Cancer. 2018; 18(1):871 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Although our previous study revealed lumbar punctured resveratrol could remarkably prolong the survival of rats bearing orthotopic glioblastomas, it also suggested the administration did not completely suppress rapid tumour growth. These evidences led us to consider that the prognosis of tumour-bearing rats may be further improved if this treatment is used in combination with neurosurgery. Therefore, we investigated the effectiveness of the combined treatment on rat orthotopic glioblastomas.
METHODS: Rat RG2 glioblastoma cells were inoculated into the brains of 36 rats. The rats were subjected to partial tumour removal after they showed symptoms of intracranial hypertension. There were 28 rats that survived the surgery, and these animals were randomly and equally divided into the control group without postoperative treatment and the LP group treated with 100 μl of 300 μM resveratrol via the LP route. Resveratrol was administered 24 h after tumour resection in 3-day intervals, and the animals received 7 treatments. The intracranial tumour sizes, average life span, cell apoptosis and STAT3 signalling were evaluated by multiple experimental approaches in the tumour tissues harvested from both groups.
RESULTS: The results showed that 5 of the 14 (35.7%) rats in the LP group remained alive over 60 days without any sign of recurrence. The remaining nine animals had a longer mean postoperative survival time (11.0 ± 2.9 days) than that of the (7.3 + 1.3 days; p < 0.05) control group. The resveratrol-treated tumour tissues showed less Ki67 labelling, widely distributed apoptotic regions, upregulated PIAS3 expression and reduced p-STAT3 nuclear translocation.
CONCLUSIONS: This study demonstrates that postoperative resveratrol administration efficiently improves the prognosis of rat advanced orthotopic glioblastoma via inhibition of growth, induction of apoptosis and inactivation of STAT3 signalling. Therefore, this therapeutic approach could be of potential practical value in the management of glioblastomas.

Jiao J, Zhang R, Li Z, et al.
Nuclear Smad6 promotes gliomagenesis by negatively regulating PIAS3-mediated STAT3 inhibition.
Nat Commun. 2018; 9(1):2504 [PubMed] Free Access to Full Article Related Publications
To date, the molecular mechanism underlying constitutive signal transducer and activator of transcription 3 (STAT3) activation in gliomas is largely unclear. In this study, we report that Smad6 is overexpressed in nuclei of glioma cells, which correlates with poor patient survival and regulates STAT3 activity via negatively regulating the Protein Inhibitors of Activated STAT3 (PIAS3). Mechanically, Smad6 interacts directly with PIAS3, and this interaction is mediated through the Mad homology 2 (MH2) domain of Smad6 and the Ring domain of PIAS3. Smad6 recruits Smurf1 to facilitate PIAS3 ubiquitination and degradation, which also depends on the MH2 domain and the PY motif of Smad6. Consequently, Smad6 reduces PIAS3-mediated STAT3 inhibition and promotes glioma cell growth and stem-like cell initiation. Moreover, the Smad6 MH2 transducible protein restores PIAS3 expression and subsequently reduces gliomagenesis. Collectively, we conclude that nuclear-Smad6 enhances glioma development by inducing PIAS3 degradation and subsequent STAT3 activity upregulation.

Ma J, Yang Y, Fu Y, et al.
PIAS3-mediated feedback loops promote chronic colitis-associated malignant transformation.
Theranostics. 2018; 8(11):3022-3037 [PubMed] Free Access to Full Article Related Publications

Saini U, Suarez AA, Naidu S, et al.
Cancer Res. 2018; 78(7):1739-1750 [PubMed] Free Access to Full Article Related Publications
The initial molecular events that lead to malignant transformation of the fimbria of the fallopian tube (FT) through high-grade serous ovarian carcinoma (HGSC) remain poorly understood. In this study, we report that increased expression of signal transducer and activator of transcription 3 (

Ray S, Coulter DW, Gray SD, et al.
Suppression of STAT3 NH
Mol Carcinog. 2018; 57(4):536-548 [PubMed] Free Access to Full Article Related Publications
Medulloblastoma (MB) is a malignant pediatric brain tumor with poor prognosis. Signal transducers and activators of transcription-3 (STAT3) is constitutively activated in MB where it functions as an oncoprotein, mediating cancer progression and metastasis. Here, we have delineated the functional role of activated STAT3 in MB, by using a cell permeable STAT3-NH

Codony-Servat J, Cuatrecasas M, Asensio E, et al.
Nuclear IGF-1R predicts chemotherapy and targeted therapy resistance in metastatic colorectal cancer.
Br J Cancer. 2017; 117(12):1777-1786 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Although chemotherapy is the cornerstone treatment for patients with metastatic colorectal cancer (mCRC), acquired chemoresistance is common and constitutes the main reason for treatment failure. Monoclonal antibodies against insulin-like growth factor-1 receptor (IGF-1R) have been tested in pre-treated mCRC patients, but results have been largely deceiving.
METHODS: We analysed time to progression, overall survival, and the mutational status of RAS, BRAF and nuclear p-IGF-1R expression by immunohistochemistry, in 470 metastatic CRC patients. The effect of IGF-1R activation and distribution was also assessed using cellular models of CRC and RNAi for functional validation.
RESULTS: Nuclear IGF-1R increased in metastatic tumours compared to paired untreated primary tumours, and significantly correlated with poor overall survival in mCRC patients. In vitro, chemo-resistant cell lines presented significantly higher levels of IGF-1R expression within the nuclear compartment, and PIAS3, a protein implicated also in the sumoylation process of intranuclear proteins, contributed to IGF-1R nuclear sequestration, highlighting the essential role of PIAS3 in this process. Intriguingly, we observed that ganitumab, an IGF-1R blocking-antibody used in several clinical trials, and dasatinib, an SRC inhibitor, increased the nuclear localisation of IGF-1R.
CONCLUSIONS: Our study demonstrates that IGF-1R nuclear location might lead to chemotherapy and targeted agent resistance.

Lin X, Lin BW, Chen XL, et al.
PAI-1/PIAS3/Stat3/miR-34a forms a positive feedback loop to promote EMT-mediated metastasis through Stat3 signaling in Non-small cell lung cancer.
Biochem Biophys Res Commun. 2017; 493(4):1464-1470 [PubMed] Related Publications
AIM: This study intented to clarify the intracellular effect of PAI-1 on Non-small cell lung cancer (NSCLC) metastasis and the precise mechanism involved.
METHODS: The metastatic properties of NSCLC cells were determined by transwell assays and wound-healing assay in vitro. The mRNA and protein expressions of genes were analyzed by Real-time qPCR and western blot, respectively. Pulmonary metastasis model of NSCLC cells was established to evaluate the pro-metastasis effect of PAI-1 and anti-metastatic effect of miR-34a in vivo. The gene targets of miR-34a were confirmed by luciferase reporter assays. Chromatin immunoprecipitation assay was employed to detect the transcriptional regulation of miR-34a. Co-immunoprecipitation assay was performed to observe the interaction of proteins.
RESULTS: PAI-1, which was elevated in NSCLC patients with recurrence and metastasis, augmented NSCLC metastasis and was negatively related to the prognosis of NSCLC. miR-34a, which was decreased in NSCLC patients with metastasis, attenuated NSCLC metastasis and was positively correlated with the prognosis of NSCLC. Moreover, PAI-1 was identified as the target gene of miR-34a and activated the Stat3 signaling pathway to promote epithelial-mesenchymal transition (EMT) in NSCLC cells. PAI-1 interacted with PIAS3 to regulate Stat3-dependent gene expression and miR-34a was transcriptionally suppressed by Stat3 to form a positive regulatory loop through Stat3 signaling.
CONCLUSION: Our findings suggest that PAI-1 and miR-34a, which can be clinically utilized as biomarkers for the clinical prognosis or diagnosis of NSCLC, are potential targets for the treatment of NSCLC.

Pastuszak-Lewandoska D, Domańska-Senderowska D, Kordiak J, et al.
Immunoexpression analysis of selected JAK/STAT pathway molecules in patients with non- small-cell lung cancer.
Pol Arch Intern Med. 2017; 127(11):758-764 [PubMed] Related Publications
INTRODUCTION    Signal transducer and activator of transcription (STAT) proteins are critically involved in tumorigenesis in various cancers, including lung cancer. OBJECTIVES    The aim of the study was to analyze the immunoexpression levels of 3 STAT proteins: STAT3, STAT5, and STAT6 in their phosphorylated forms (pSTATs), STAT inhibitors PIAS3 and SOCS3, and additionally cyclooxygenase 2 (COX‑2), as potential diagnostic and prognostic markers in lung cancer. PATIENTS AND METHODS    The study included 71 patients diagnosed with non- small-cell lung cancer (NSCLC). The immunoexpression levels of the proteins were assessed in lung tissue samples, using an enzyme‑linked immunosorbent assay. Tumors were staged using the postoperative TNM classification. RESULTS    All studied STATs were overexpressed in 54% to 55% of NSCLC specimens. Significantly higher STAT3 and STAT6 immunoexpression levels were observed in squamous cell carcinoma. Significant differences between NSCLC samples and controls were found for STAT5. Significantly higher STAT5 levels were observed in pT2 tumors. The COX‑2 overexpression was observed in 55% of NSCLC specimens and was significantly higher in T2 tumors. STAT inhibitors were underexpressed in 56% to 58% of NSCLC specimens. The PIAS3 immunoexpression was significantly lower in non-squamous cell carcinoma. The SOCS3 level was significantly lower in smaller tumors (pT1). Negative correlations between STAT5 and PIAS3 levels, as well as between STAT6 and SOCS levels, and a positive correlation between STAT5 and COX-2 levels were observed. CONCLUSIONS    The deregulated expression of the studied pSTATs and their inhibitors may be involved in the development and progression of lung cancer. The observed differences between the histotypes suggest the potential usefulness of STAT proteins as diagnostic markers. Our results may contribute to the search for targets in lung cancer therapy.

Carabia J, Carpio C, Abrisqueta P, et al.
Microenvironment regulates the expression of miR-21 and tumor suppressor genes PTEN, PIAS3 and PDCD4 through ZAP-70 in chronic lymphocytic leukemia.
Sci Rep. 2017; 7(1):12262 [PubMed] Free Access to Full Article Related Publications
Chronic lymphocytic leukemia (CLL) cells are highly dependent on microenvironment, being the BCR pathway one key player in this crosstalk. Among proteins participating, ZAP-70 enhances response to microenvironmental stimuli. MicroRNA-21 (miR-21) is overexpressed in diverse neoplasias including CLL, where it has been associated to refractoriness to fludarabine and to shorter time to progression and survival. To further elucidate the role of ZAP-70 in the biology of CLL, we studied its involvement in miR-21 regulation. MiR-21 expression was higher in CLL cells with high ZAP-70. Ectopic expression of ZAP-70 induced transcription of miR-21 via MAPK and STAT3, which subsequently induced downregulation of tumor suppressors targeted by miR-21. The co-culture of primary CLL cells mimicking the microenvironment induced ZAP-70 and miR-21 expression, as well as downregulation of miR-21 targets. Interestingly, the increase in miR-21 after co-culture was significantly impaired by ibrutinib, indicating that the BCR signaling pathway is involved in its regulation. Finally, survival of CLL cells induced by the co-culture correlated with miR-21 upregulation. In conclusion, stimuli from the microenvironment regulate miR-21 and its targeted tumor suppressor genes via a signaling pathway involving ZAP-70, thus contributing to the cytoprotection offered by the microenvironment particularly observed in CLL cells expressing ZAP-70.

Wang C, Ba X, Guo Y, et al.
MicroRNA-199a-5p promotes tumour growth by dual-targeting PIAS3 and p27 in human osteosarcoma.
Sci Rep. 2017; 7:41456 [PubMed] Free Access to Full Article Related Publications
Osteosarcoma (OS) is the most common primary bone malignancy and remains a leading cause of cancer-related deaths in adolescents. Emerging evidence indicates that microRNAs (miRNAs) are correlated with clinical and biological characteristics of OS. However, the involvement of miR-199a-5p in OS development remains unclear. In this study, we examined the function of miR-199a-5p in vitro and in vivo. The results showed that miR-199a-5p was significantly up-regulated in OS patient tissues and cells. The inhibition of miR-199a-5p led to a significant decrease in cell proliferation and tumour growth. We further demonstrated that miR-199a-5p could directly bind to the 3'UTRs of the mRNA of both PIAS3 and p27 and mediate a decrease in the protein levels of PIAS3 and p27, thereby stimulating STAT3 activation and cell cycle progression in OS cells. Rescue experiments of PIAS3 and p27 further revealed that PIAS3 and p27 were functional targets of miR-199a-5p. Moreover, enhancing the expressions of both PIAS3 and p27 using miR-199a-5p-targeted inhibitors in an OS xenograft model was shown to be a promising approach for OS clinical therapy. Our findings indicate that the pathway of miR-199a-5p targeting both PIAS3 and p27 is a possible mechanism that contributes to tumour growth in OS.

Zhang C, Mukherjee S, Tucker-Burden C, et al.
TRIM8 regulates stemness in glioblastoma through PIAS3-STAT3.
Mol Oncol. 2017; 11(3):280-294 [PubMed] Free Access to Full Article Related Publications
Glioblastoma (GBM) is the most malignant form of primary brain tumor, and GBM stem-like cells (GSCs) contribute to the rapid growth, therapeutic resistance, and clinical recurrence of these fatal tumors. STAT3 signaling supports the maintenance and proliferation of GSCs, yet regulatory mechanisms are not completely understood. Here, we report that tri-partite motif-containing protein 8 (TRIM8) activates STAT3 signaling to maintain stemness and self-renewing capabilities of GSCs. TRIM8 (also known as 'glioblastoma-expressed ring finger protein') is expressed equally in GBM and normal brain tissues, despite its hemizygous deletion in the large majority of GBMs, and its expression is highly correlated with stem cell markers. Experimental knockdown of TRIM8 reduced GSC self-renewal and expression of SOX2, NESTIN, and p-STAT3, and promoted glial differentiation. Overexpression of TRIM8 led to higher expression of p-STAT3, c-MYC, SOX2, NESTIN, and CD133, and enhanced GSC self-renewal. We found that TRIM8 activates STAT3 by suppressing the expression of PIAS3, an inhibitor of STAT3, most likely through E3-mediated ubiquitination and proteasomal degradation. Interestingly, we also found that STAT3 activation upregulates TRIM8, providing a mechanism for normalized TRIM8 expression in the setting of hemizygous gene deletion. These data demonstrate that bidirectional TRIM8-STAT3 signaling regulates stemness in GSC.

Li C, Li H, Zhang P, et al.
SHP2, SOCS3 and PIAS3 Expression Patterns in Medulloblastomas: Relevance to STAT3 Activation and Resveratrol-Suppressed STAT3 Signaling.
Nutrients. 2016; 9(1) [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Activated STAT3 signaling is critical for human medulloblastoma cells. SHP2, SOCS3 and PIAS3 are known as the negative regulators of STAT3 signaling, while their relevance to frequent STAT3 activation in medulloblastomas remains unknown.
METHODS: Tissue microarrays were constructed with 17 tumor-surrounding noncancerous brain tissues and 61 cases of the classic medulloblastomas, 44 the large-cell medulloblastomas, and 15 nodular medulloblastomas, which were used for immunohistochemical profiling of STAT3, SHP2, SOCS3 and PIAS3 expression patterns and the frequencies of STAT3 nuclear translocation. Three human medulloblastoma cell lines (Daoy, UW228-2 and UW228-3) were cultured with and without 100 μM resveratrol supplementation. The influences of resveratrol in SHP2, SOCS3 and PIAS3 expression and SOCS3 knockdown in STAT3 activation were analyzed using multiple experimental approaches.
RESULTS: SHP2, SOCS3 and PIAS3 levels are reduced in medulloblastomas in vivo and in vitro, of which PIAS3 downregulation is more reversely correlated with STAT3 activation. In resveratrol-suppressed medulloblastoma cells with STAT3 downregulation and decreased incidence of STAT3 nuclear translocation, PIAS3 is upregulated, the SHP2 level remains unchanged and SOCS3 is downregulated. SOCS3 proteins are accumulated in the distal ends of axon-like processes of resveratrol-differentiated medulloblastoma cells. Knockdown of SOCS3 expression by siRNA neither influences cell proliferation nor STAT3 activation or resveratrol sensitivity but inhibits resveratrol-induced axon-like process formation.
CONCLUSION: Our results suggest that (1) the overall reduction of SHP2, SOCS3 and PIAS3 in medulloblastoma tissues and cell lines; (2) the more inverse relevance of PIAS3 expression with STAT3 activation; (3) the favorable prognostic values of PIAS3 for medulloblastomas and (4) the involvement of SOCS3 in resveratrol-promoted axon regeneration of medulloblastoma cells.

Pan CM, Wang ML, Chiou SH, et al.
Oncostatin M suppresses metastasis of lung adenocarcinoma by inhibiting SLUG expression through coordination of STATs and PIASs signalings.
Oncotarget. 2016; 7(37):60395-60406 [PubMed] Free Access to Full Article Related Publications
Oncostatin M (OSM) is linked with multiple biological responses including growth and differentiation. Previous reports showed inhibitory effects of OSM in tumor progression while others showed promoting effects. The dual role of OSM in the development of various cancers is still unclear. We previously described OSM-mediated SLUG suppression, leading to repressed metastasis of lung adenocarcinoma (LAC) cells. However, the underlying mechanism remains elusive. Here, we showed that OSM suppresses SLUG express in LAC cells through a STAT1-dependent transcriptional inhibition. Knockdown of STAT1 reversed the OSM-suppressed SLUG expression and rescued the OSM-mediated inhibition of cell proliferation, migration, and invasion in vitro, as well as pulmonary metastasis in vivo. STAT1 suppressed SLUG transcription through binding to its promoter region in response to OSM. Furthermore, PIAS4, a co-repressor of STAT, and HDAC1 were able to bind to STAT1 on SLUG promoter region, resulting in reduced H3K9 acetylation and suppressed SLUG expression upon OSM treatment. In contrast, PIAS3 bound to activated STAT3, another effector of OSM, in response to OSM and blocked the binding of STAT3 to SLUG promoter region, preventing STAT3-dependent activation of SLUG transcription. Our findings suggested that OSM suppresses SLUG expression and tumor metastasis of LAC through inducing the inhibitory effect of the STAT1-dependent pathway and suppressing the activating effect of STAT3-dependent signaling. These results can serve as a scientific basis for the potential therapeutic intervention of OSM in cancer cells.

Ko JH, Ho Baek S, Nam D, et al.
3-Formylchromone inhibits proliferation and induces apoptosis of multiple myeloma cells by abrogating STAT3 signaling through the induction of PIAS3.
Immunopharmacol Immunotoxicol. 2016; 38(5):334-43 [PubMed] Related Publications
Constitutive activation of signal transducer and activator of transcription 3 (STAT3) is frequently observed and closely linked with proliferation, survival, metastasis and angiogenesis of various cancer cells, and thus its inhibition can be considered a potential therapeutic strategy. We found that 3-formylchromone (3FC) inhibited both constitutive and inducible STAT3 activation in multiple myeloma (MM) cells. Besides the inhibition of STAT3 phosphorylation, 3FC also abrogated constitutive activity and nuclear translocation of STAT3. This suppression was mediated through the inhibition of phosphorylation of Janus-activated kinase (JAK) 1/2 and Src. Furthermore, 3FC induced the expression of the protein inhibitors of activated STAT3 (PIAS3), and gene silencing of the PIAS3 by small interfering RNA abolished the ability of 3FC to inhibit STAT3 activation, suggesting a critical role for PIAS3 in the action of 3FC. 3FC also downregulated the expression of STAT3-regulated gene products such as Bcl-2, Bcl-xl, Mcl-1, Survivin, inhibitor of apoptosis protein-1 (IAP-1), Cyclin D1, cyclooxygenase-2 (COX-2), and matrix metalloproteinases-9 (MMP-9) in MM cells. This correlated with induction of substantial apoptosis as indicated by an increase in the sub-G1 cell population and caspase-3 induced poly ADP ribose polymerase (PARP) cleavage. Overall, these results suggest that 3FC is a novel blocker of STAT3 activation pathway thus may have a potential in therapy of MM and other cancers.

Huang G, Wu X, Li S, et al.
The long noncoding RNA CASC2 functions as a competing endogenous RNA by sponging miR-18a in colorectal cancer.
Sci Rep. 2016; 6:26524 [PubMed] Free Access to Full Article Related Publications
Recent evidence highlights the crucial regulatory roles of long noncoding RNAs (lncRNA) in tumor biology. In colorectal cancer (CRC), the expression of several lncRNAs is dysregulated and play essential roles in CRC tumorigenesis. However, the potential biological roles and regulatory mechanisms of the novel human lncRNA, CASC2 (cancer susceptibility candidate 2), in tumor biology are poorly understood. In this study, CASC2 expression was significantly decreased in CRC tissues and CRC cell lines, and decreased expression was significantly more frequent in patients with advanced tumor-node-metastasis stage disease (TNM III and IV) (P = 0.028). Further functional experiments indicate that CASC2 could directly upregulate PIAS3 expression by functioning as a competing endogenous RNA (ceRNA) for miR-18a. This interactions leads to the de-repression of genes downstream of STAT3 and consequentially inhibition of CRC cell proliferation and tumor growth in vitro and in vivo by extending the G0/G1-S phase transition. Taken together, these observations suggest CASC2 as a ceRNA plays an important role in CRC pathogenesis and may serve as a potential target for cancer diagnosis and treatment.

Yang SF, Hou MF, Chen FM, et al.
Prognostic value of protein inhibitor of activated STAT3 in breast cancer patients receiving hormone therapy.
BMC Cancer. 2016; 16:20 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Deregulated signal transducer and activator of transcription 3 (STAT3) signaling has been well documented in certain cancers. Alterations in specific negative regulators, such as protein inhibitor of activated STAT3 (PIAS3), may contribute to cancer development.
METHODS: The expression of total PIAS3 was determined in 100 paired cancerous and non-cancerous breast tissues by immunoblotting and was statistically analyzed along with the clinicopathological characteristics and overall survival of the patients. XTT, immunoblotting, and chromatin immunoprecipitation (Chip) were used to examine the biological effect of PIAS3 in breast cancer cells.
RESULTS: Hormone therapy failed to improve the overall survival in patients presenting with increased PIAS3 expression. Ectopic PIAS3 overexpression increased the proliferation and expression of cyclin D1 in estrogen receptor (ER)-positive MCF-7 and T47D cells, but decreased those in ER-negative MDA-MB-231 and SKBR3 cells. Furthermore, PIAS3 overexpression attenuated cytotoxicity of tamoxifen and increased proliferation and cyclin D1 expression in MCF-7 cells. PIAS3 also decreased the binding of itself on the cyclin D1 promoter and this decreased binding was not affected by tamoxifen.
CONCLUSION: PIAS3 may serve as a biomarker for predicting hormone therapy stratification, although it is limited to those breast cancer patients receiving hormone therapy.

Chin DW, Sakurai M, Nah GS, et al.
RUNX1 haploinsufficiency results in granulocyte colony-stimulating factor hypersensitivity.
Blood Cancer J. 2016; 6:e379 [PubMed] Free Access to Full Article Related Publications
RUNX1/AML1 is among the most commonly mutated genes in human leukemia. Haploinsufficiency of RUNX1 causes familial platelet disorder with predisposition to myeloid malignancies (FPD/MM). However, the molecular mechanism of FPD/MM remains unknown. Here we show that murine Runx1(+/-) hematopoietic cells are hypersensitive to granulocyte colony-stimulating factor (G-CSF), leading to enhanced expansion and mobilization of stem/progenitor cells and myeloid differentiation block. Upon G-CSF stimulation, Runx1(+/-) cells exhibited a more pronounced phosphorylation of STAT3 as compared with Runx1(+/+) cells, which may be due to reduced expression of Pias3, a key negative regulator of STAT3 signaling, and reduced physical sequestration of STAT3 by RUNX1. Most importantly, blood cells from a FPD patient with RUNX1 mutation exhibited similar G-CSF hypersensitivity. Taken together, Runx1 haploinsufficiency appears to predispose FPD patients to MM by expanding the pool of stem/progenitor cells and blocking myeloid differentiation in response to G-CSF.

Zhang P, Yang B, Yao YY, et al.
PIAS3, SHP2 and SOCS3 Expression patterns in Cervical Cancers: Relevance with activation and resveratrol-caused inactivation of STAT3 signaling.
Gynecol Oncol. 2015; 139(3):529-35 [PubMed] Related Publications
OBJECTIVE: Resveratrol inhibits cervical cancer (CC) cells by blocking STAT3 signaling. However, the mechanism of resveratrol-induced STAT3 inactivation remains largely unknown. SHP2, PIAS3, and SOCS3 are STAT3 negative regulators; therefore, their statuses in cervical adenocarcinoma (HeLa) and squamous cell carcinoma (SiHa and C33A) cell lines without and with resveratrol treatment and their correlation with STAT3 activation in CC specimens were investigated.
METHODS: MTT and TUNEL assays were used to check the resveratrol sensitivity of CC cells, and immunocytochemical staining, Western blotting, and RT-PCR were used to analyze SHP2, PIAS3, and SOCS3 expression and the intracellular distribution of STAT3. Tissue microarray based immunohistochemical staining was performed to investigate potential correlations between SHP2, PIAS3, and SOCS3 expression and STAT3 activation.
RESULTS: PIAS3 and SOCS3 were found to be weakly expressed in CC cells and upregulated by resveratrol; this was accompanied by inhibition of STAT3 signaling. The SHP2 level remained unchanged in all three cell lines after resveratrol treatment. STAT3 nuclear translocation was more frequent in adenocarcinomas and squamous cell carcinomas than that of their noncancerous counterparts. The SOCS3 level and detection rate were higher in noncancerous squamous cells (but not in glandular epithelia) compared with their cancerous counterparts. The phospho-SHP2 detection rate was similar in noncancerous and tumor tissues of squamous and glandular origins; however, PIAS3 levels were distinct.
CONCLUSIONS: Of the three STAT3 negative regulators, PIAS3 correlated most negatively with STAT3 nuclear translocation and may inhibit STAT3 signaling in both histological CC subtypes. PIAS3 responsiveness may reflect greater resveratrol sensitivity and improved therapeutic outcome in CCs.

Pitari MR, Rossi M, Amodio N, et al.
Inhibition of miR-21 restores RANKL/OPG ratio in multiple myeloma-derived bone marrow stromal cells and impairs the resorbing activity of mature osteoclasts.
Oncotarget. 2015; 6(29):27343-58 [PubMed] Free Access to Full Article Related Publications
miR-21 is an oncogenic microRNA (miRNA) with an emerging role as therapeutic target in human malignancies, including multiple myeloma (MM). Here we investigated whether miR-21 is involved in MM-related bone disease (BD). We found that miR-21 expression is dramatically enhanced, while osteoprotegerin (OPG) is strongly reduced, in bone marrow stromal cells (BMSCs) adherent to MM cells. On this basis, we validated the 3'UTR of OPG mRNA as miR-21 target. Constitutive miR-21 inhibition in lentiviral-transduced BMSCs adherent to MM cells restored OPG expression and secretion. Interestingly, miR-21 inhibition reduced RANKL production by BMSCs. Overexpression of protein inhibitor of activated STAT3 (PIAS3), which is a direct and validated target of miR-21, antagonized STAT3-mediated RANKL gene activation. Finally, we demonstrate that constitutive expression of miR-21 inhibitors in BMSCs restores RANKL/OPG balance and dramatically impairs the resorbing activity of mature osteoclasts. Taken together, our data provide proof-of-concept that miR-21 overexpression within MM-microenviroment plays a crucial role in bone resorption/apposition balance, supporting the design of innovative miR-21 inhibition-based strategies for MM-related BD.

Siatecka M, Soni S, Planutis A, Bieker JJ
Transcriptional activity of erythroid Kruppel-like factor (EKLF/KLF1) modulated by PIAS3 (protein inhibitor of activated STAT3).
J Biol Chem. 2015; 290(15):9929-40 [PubMed] Free Access to Full Article Related Publications
Erythroid Kruppel-like factor (EKLF or KLF1) is a transcription factor crucial for red cell development that is directly involved in regulation of a large number of erythroid genes. EKLF serves mostly as an activator of expression of these genes; however, it can act also as a repressor. Here, we present evidence that EKLF interacts with proteins from the PIAS (protein inhibitor of activated STAT) family that convey repressive activity to EKLF in the absence of sumoylation. Our studies identify PIAS3 as a transcriptional corepressor of EKLF for at least a subset of its target genes during erythropoiesis (e.g. β-globin, α-hemoglobin stabilizing protein). We demonstrate an interaction between EKLF and PIAS proteins confirmed by in vivo coimmunoprecipitation assays with both exogenous and endogenous proteins. We identified an LXXLL signature motif located near the N terminus of PIAS proteins that, although not involved in the EKLF-PIAS3 interaction, is required for the transrepression activity. Knockdown of endogenous PIAS3 accelerates differentiation of both murine erythroleukemia cells, as well as fetal liver cells, whereas an increase in PIAS3 levels inhibits this increase. Using chromatin immunoprecipitation assays, we show that PIAS3 preferentially occupies the β-globin promoter in undifferentiated murine erythroleukemia cells. Together these results demonstrate that an interaction between EKLF and PIAS3 provides a novel mode of regulation of EKLF activity in the absence of sumolylation and furthermore shows an important involvement of PIAS proteins in erythropoiesis.

Ran J, Wang Y, Zhang W, et al.
Research on the bioactivity of isoquercetin extracted from marestail on bladder cancer EJ cell and the mechanism of its occurrence.
Artif Cells Nanomed Biotechnol. 2016; 44(3):859-64 [PubMed] Related Publications
Research studies in recent years have found that isoquercetin has an inhibiting effect on multiple carcinogens, but research studies filed on isoquercetin in bladder cancer are quite few. This paper observed the influence of isoquercetin on biological activity of the EJ cell of bladder cancer through HC dyeing and trypan blue counting, studied the EJ cell cycle by flow cytometry (FCM), and then analyzed the influence of isoquercetin and its effect on the protein expression of STAT3 and STAT3-inhibiting factors (PIAS3) in EJ cells. Research has shown that isoquercetin has an inhibitory effect on the EJ cells of bladder cancer, but it is not obvious.

Dai X, Ahn KS, Kim C, et al.
Ascochlorin, an isoprenoid antibiotic inhibits growth and invasion of hepatocellular carcinoma by targeting STAT3 signaling cascade through the induction of PIAS3.
Mol Oncol. 2015; 9(4):818-33 [PubMed] Free Access to Full Article Related Publications
Deregulated activation of oncogenic transcription factors such as signal transducer and activator of transcription 3 (STAT3) plays a pivotal role in proliferation and survival of hepatocellular carcinoma (HCC). Thus, agents which can inhibit STAT3 activation may have an enormous potential for treatment of HCC patients. Hence, in the present report, we investigated the effect of ascochlorin (ASC), an isoprenoid antibiotic on STAT3 activation cascade in various HCC cell lines and orthotopic mouse model. We observed that ASC could substantially inhibit both constitutive and IL-6/EGF inducible STAT3 activation as well as reduce its DNA binding ability. ASC increased the expression of protein inhibitor of activated STAT3 (PIAS3) which could bind to STAT3 DNA binding domain and thereby down-regulate STAT3 activation. Deletion of PIAS3 gene by siRNA abolished the ability of ASC to inhibit STAT3 activation and induce apoptosis in HCC cells. ASC also modulated the expression of diverse STAT3-regulated oncogenic gene products. Finally, when administered intraperitoneally, ASC also inhibited tumor growth in an orthotopic HCC mouse model and reduced STAT3 activation in tumor tissues. Overall our results indicate that ASC mediates its anti-tumor effects predominantly through the suppression of STAT3 signaling cascade, and can form the basis of novel therapy for HCC patients.

Abbas R, McColl KS, Kresak A, et al.
PIAS3 expression in squamous cell lung cancer is low and predicts overall survival.
Cancer Med. 2015; 4(3):325-32 [PubMed] Free Access to Full Article Related Publications
Unlike lung adenocarcinoma, little progress has been made in the treatment of squamous cell lung carcinoma (SCC). The Cancer Genome Atlas (TCGA) has recently reported that receptor tyrosine kinase signaling pathways are altered in 26% of SCC tumors, validating the importance of downstream Signal Transducers and Activators of Transcription 3 (STAT3) activity as a prime therapeutic target in this cancer. In the present report we examine the status of an endogenous inhibitor of STAT3, called Protein Inhibitor of Activated STAT3 (PIAS3), in SCC and its potential role in this disease. We examine PIAS3 expression in SCC tumors and cell lines by immunohistochemistry of a tissue microarray and western blotting. PIAS3 mRNA expression and survival data are analyzed in the TCGA data set. SCC cell lines are treated with curcumin to regulate PIAS3 expression and cell growth. PIAS3 protein expression is decreased in a majority of lung SCC tumors and cell lines. Analysis of PIAS3 mRNA transcript levels demonstrated that low PIAS3 levels predicted poor survival; Cox regression analysis revealed a hazard ratio of 0.57 (95% CI: 0.37-0.87), indicating a decrease in the risk of death by 43% for every unit elevation in PIAS3 gene expression. Curcumin treatment increased endogenous PIAS3 expression and decreased cell growth and viability in Calu-1 cells, a model of SCC. Our results implicate PIAS3 loss in the pathology of lung SCC and raise the therapeutic possibility of upregulating PIAS3 expression as a single target that can suppress signaling from the multiple receptor tyrosine kinase receptors found to be amplified in SCC.

Pastuszak-Lewandoska D, Domańska D, Czarnecka KH, et al.
Expression of STAT5, COX-2 and PIAS3 in correlation with NSCLC histhopathological features.
PLoS One. 2014; 9(8):e104265 [PubMed] Free Access to Full Article Related Publications
Signal transducers and activators of transcription (STATs), their inhibitors and cyclooxygenase-2 (COX-2) participate in transformations of many various types of cancers. The aim of the present study was to evaluate the relationship between STAT5A/B, COX-2, and PIAS3 mRNA expression and tumor staging, metastasis status, and histopathological subtype in 71 patients with confirmed non-small cell lung cancer (NSCLC) diagnosis. Total RNA was isolated from NSCLC tissue samples and the expression of the studied genes was assessed using TaqMan probes in real-time PCR assay. The expression levels of STAT5A, STAT5B, and COX-2 genes were increased in 69%, 79%, and 71% NSCLC samples respectively, while PIAS3 expression was decreased in the majority (69%) of the studied tissues. Statistically significant differences were observed between STAT5 isoforms (P = 0.0008), with higher expression of STAT5B. We found statistically significant positive correlation between STAT5B and COX-2 (rho = 0.045), and significant negative correlation between STAT5B and PIAS3 (rho = -0.049). The negative correlation between STAT5B and PIAS3 (rho = -0.43) was also observed in T2a+T2b tumor group. Additionally, STAT5B and COX-2 expression levels were significantly different between T1a+T1b and T2a+T2b tumors (P = 0.002 and P = 0.041, respectively), with higher expression of both genes in T2 tumor stage. PIAS3 expression was significantly lower in NSCC subtype as compared with SCC subtype (P = 0.017). Also, STAT5A and STAT5B immunoexpression was assessed, and the results indicated significantly higher protein levels in NSCLC patients as compared with controls (P = 0.048 and P = 0.034, respectively). High STAT5B immunoexpression was positively correlated with STAT5B gene expression in tumors (rho = 0.755). STAT5B protein level was also significantly higher in T2a+T2b tumors, reflecting high STAT5B gene expression in this group. There was no statistically significant association between mRNA and protein expression levels of the studied genes and patients' characteristics: age, gender, smoking. The obtained results highlight the importance of the genes STAT5B and COX-2 in lung cancer progression.

Dabir S, Kluge A, Kresak A, et al.
Low PIAS3 expression in malignant mesothelioma is associated with increased STAT3 activation and poor patient survival.
Clin Cancer Res. 2014; 20(19):5124-32 [PubMed] Related Publications
PURPOSE: Deregulation of STAT3 activation is a hallmark of many cancer cells, and the underlying mechanisms are subject to intense investigation. We examined the extent of PIAS3 expression in mesothelioma cells and human tumor samples and determined the functional effects of PIAS3 expression on STAT3 signaling.
EXPERIMENTAL DESIGN: We evaluated the expression of PIAS3 in mesothelioma tumors from patients and correlated the expression levels with the course of the disease. We also measured the effects of enhanced PIAS3 activity on STAT3 signaling, cellular growth, and viability in cultured mesothelioma cells.
RESULTS: Gene expression databases revealed that mesotheliomas have the lowest levels of PIAS3 transcripts among solid tumors. PIAS3 expression in human mesothelioma tumors is significantly correlated with overall survival intervals (P = 0.058). The high expression of PIAS3 is predictive of a favorable prognosis and decreases the probability of death within one year after diagnosis by 44%. PIAS3 expression is functionally linked to STAT3 activation in mesothelioma cell lines. STAT3 downregulation with siRNA or enhanced expression of PIAS3 both inhibited mesothelioma cell growth and induced apoptosis. Mesothelioma cells are sensitive to curcumin and respond by the induction of PIAS3. Corroborative evidence has been obtained from STAT3 inhibition experiments. Exposure of the cells to a peptide derived from the PIAS3 protein that interferes with STAT3 function resulted in apoptosis induction and the inhibition of cell growth.
CONCLUSION: These results suggest that PIAS3 protein expression impacts survival in patients with mesothelioma and that PIAS3 activation could become a therapeutic strategy. Clin Cancer Res; 20(19); 5124-32. ©2014 AACR.

Yu T, Lu Q, Ou X, et al.
Association of sedentary behavior with the expression levels of biomarkers in colorectal cancer: clinical analysis of 228 patients.
Tohoku J Exp Med. 2014; 232(3):167-76 [PubMed] Related Publications
There is an association between sedentary behavior and the risk of colorectal cancer (CRC), but the underlying mechanism is unclear. CRC is characterized by the changes in the expression levels of biomarkers, including voltage-gated proton channel Hv1, matrix-remodeling associated 5 (MXRA5), DEK (inducing positive supercoils into circular DNA) and protein inhibitor of activated signal transducer and activators of transcription 3 (PIAS3). Thus, sedentary behavior may affect the expression levels of these biomarkers in the colorectal tissue. Here, we recruited 228 CRC patients (128 males, 57.8 ± 7.8 years; 100 females, 57.7 ± 7.5 years) and 80 healthy subjects (48 males, 57.5 ± 6.8 years; 32 females, 56.9 ± 6.5 years) from March 7th, 2010 to May 6th, 2012. All the subjects were unrelated Han Chinese with the similar cultural and economic background. All the subjects were interviewed concerning sedentary time (sitting time categories: less than 1, 1-3, 4-6, and more than 6 h/day). The daily sedentary time of most CRC patients was more than 4 h/day, while the sedentary time of most healthy subjects was less than 3 h/day. The expression levels of Hv1, MXRA5 and DEK mRNAs and proteins were higher in CRC tissues and the levels of PIAS3 mRNA and protein were lower when the daily sedentary time was longer in CRC patients (p < 0.05). The daily sedentary time was correlated with the protein levels of CRC biomarkers. Furthermore, the sedentary time was positively related with body mass index but not daily calorie intake.

Zhao Z, Wu L, Shi H, Wu C
p53 N‑terminal binding and stabilisation by PIAS3 inhibits MDM2‑induced p53 ubiquitination and regulates cell growth.
Mol Med Rep. 2014; 9(5):1903-8 [PubMed] Related Publications
Mouse double minute 2 homolog (MDM2) binds to p53 through the 1-52 amino acid region of p53, in order to ubiquitinate p53. MDM2 thus destabilises p53 and inhibits the effect of p53 on cell cycle arrest and apoptosis. In the present study, the 1-52 amino acid region of the wild-type (wt) p53 protein was stably expressed in H1299 cells. The lysate of the transfected cells was then analysed using co-immunoprecipitation. A specific fraction of the precipitate was subjected to mass spectrometry analysis, which revealed that p53 bound to protein inhibitor of activated STAT3 (PIAS3). To the best of our knowledge, the present study is the first to report that the interaction of PIAS3 with p53 occurs through the 1-52 amino acid region of p53. Overexpression of PIAS3 in the A549 wt p53-expressing cell line was found to significantly increase the half‑life of p53 in the presence of cycloheximide, an inhibitor of protein synthesis. However, PIAS3 overexpression did not affect p53 mRNA levels. Furthermore, PIAS3 overexpression was observed to decrease p53 ubiquitination. Protein-protein interaction analysis revealed that PIAS3 binds to the 1-52 amino acid region of p53, thus disrupts the formation of the p53‑MDM2 complex. In addition, overexpression of PIAS3 in A549 cells was found to enhance the transcription of the p53‑transactivated target p21/waf1, due to p53 accumulation, which led to an increase in p53 binding to the p21 gene promoter. These findings indicate that this newly identified p53‑PIAS3 interaction through the 1-52 amino acid region of p53, reduces p53‑MDM2 complex formation, which not only increases the half-life of p53, but also its transactivation of target genes.

Nam D, Song J, Kim SM, et al.
8-hydrocalamenene, derived from Reynoutria elliptica, suppresses constitutive STAT3 activation, inhibiting proliferation and enhancing chemosensitization of human multiple myeloma cells.
J Med Food. 2014; 17(3):365-73 [PubMed] Free Access to Full Article Related Publications
The identification of the active compounds of herbal medicines and the molecular targets of those compounds is an attractive therapeutic objective. Reynoutria elliptica has been used for the treatment of various inflammatory diseases as a Korean folk remedy. Based on the evidence that anti-inflammatory agents frequently exert antiproliferative activity, we tested two sesquiterpene derivatives, 8-hydrocalamenene (HC) and 8,14-dihydrocalamenene (DHC), for their ability to induce apoptosis and suppress signal transducer and activator of transcription 3 (STAT3) activation in multiple myeloma (MM) U266 cells. We found that HC inhibited cell viability in U266, but not in peripheral blood mononuclear cells. HC exerted significant cytotoxicity and induced substantial subG1-phase arrest and apoptosis as compared with DHC. HC inhibited the expression of gene products involved in antiapoptosis (Bcl-2 and Bcl-xL), proliferation (cyclin D1), and invasion (MMP-9), all of which are known to be regulated by STAT3. Furthermore, HC up-regulated cyclin-dependent kinase inhibitor p21 and induced apoptosis through the activation of caspase-8, -9, and -3 in U266 cells. Interestingly, HC blocked constitutive STAT3 activation through the inhibition of activation of upstream kinases Janus-like kinase 1 (JAK1), JAK2, and c-Src and up-regulated PIAS3. Deletion of STAT3 reversed cytotoxic effects and the down-regulation of cyclin D1 and c-myc by HC in MM cells. Finally, this sesquiterpene significantly synergized the cytotoxic and apoptotic effects of bortezomib in U266 cells. Taken together, these results suggest that HC is a novel blocker of STAT3 activation which may have a potential in the prevention and treatment of MM.

Cao Q, Li YY, He WF, et al.
Interplay between microRNAs and the STAT3 signaling pathway in human cancers.
Physiol Genomics. 2013; 45(24):1206-14 [PubMed] Related Publications
MicroRNAs (miRNAs, also miR) are a class of noncoding endogenous RNAs that regulate gene expression through binding to protein-coding messenger RNA (mRNA) molecules, predominantly within the 3'-untranslated region (3'-UTR). Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates a battery of genes involved in regulating a variety of biological processes. There is a growing body of evidence demonstrating that miRNAs are closely associated with the STAT3 signaling pathway. In this review, we focus on interactions between miRNAs and the STAT3 signaling pathway, focusing on their reciprocal regulation and roles in cancer. For instance, several papers independently support the existence of regulatory feedback loops between miRNAs and the STAT3 pathway in different cancer contexts including IL-6-STAT3-miR-24/miR-629-HNF4α-miR-124 and IL-6R-STAT3-NF-κB-Lin-28-let-7a. Furthermore, several miRNA components are reported to be involved in STAT3-mediated tumorigenesis, for example miR-21, miR-155, and miR-181b. Through binding to STAT3-binding sites within the promoters of these oncomiRs, STAT3 activates their transcription and mediates tumorigenesis. Some miRNAs directly modulate STAT3 activity through targeting the STAT3 3'-UTR; other miRNAs target SOCS, PIAS3, and EGFR genes, which encode proteins that regulate the STAT3 signaling pathway. Given that miRNAs represent a newly discovered class of regulatory molecules, investigating their biological functions and contribution to pathologies caused by STAT3 dysregulation is essential to improve our understanding of tumorigenesis and to develop novel anticancer therapeutics. The more we can learn about miRNAs-STAT3 interactions, the better able we will be to manipulate them for developing cancer therapeutics.

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