Gene Summary

Gene:STC1; stanniocalcin 1
Aliases: STC
Summary:This gene encodes a secreted, homodimeric glycoprotein that is expressed in a wide variety of tissues and may have autocrine or paracrine functions. The gene contains a 5' UTR rich in CAG trinucleotide repeats. The encoded protein contains 11 conserved cysteine residues and is phosphorylated by protein kinase C exclusively on its serine residues. The protein may play a role in the regulation of renal and intestinal calcium and phosphate transport, cell metabolism, or cellular calcium/phosphate homeostasis. Overexpression of human stanniocalcin 1 in mice produces high serum phosphate levels, dwarfism, and increased metabolic rate. This gene has altered expression in hepatocellular, ovarian, and breast cancers. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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: STC1 (cancer-related)

Wang Y, Qi Z, Zhou M, et al.
Stanniocalcin‑1 promotes cell proliferation, chemoresistance and metastasis in hypoxic gastric cancer cells via Bcl‑2.
Oncol Rep. 2019; 41(3):1998-2008 [PubMed] Related Publications
Gastric cancer (GC) is one of the most lethal diseases worldwide, but the mechanism of GC development remains elusive. In the present study, the roles of stanniocalcin‑1 (STC1) in GC were investigated. It was demonstrated that overexpression of STC1 mRNA and protein were associated with poor survival of patients with GC. The expression of STC1 was enhanced in hypoxic GC cells and overexpression of STC1 facilitated cell proliferation in hypoxia but not in normoxia. Furthermore, STC1 promoted chemoresistance, migration and invasion in hypoxia. Upregulating the expression of STC1 enhanced the expression of B cell lymphoma (Bcl)‑2, neural‑cadherin and matrix metalloproteinase‑2, whereas it reduced the levels of cytochrome c, cleaved‑caspase‑9, cleaved‑caspase‑3 and epithelial‑cadherin. However, downregulation of STC1 altered the expression of these proteins in the opposite direction. Furthermore, disturbing the expression of Bcl‑2 partly reversed the changes to these proteins and also the pro‑proliferation, anti‑apoptosis and pro‑invasion potential of STC1. In vivo experiments indicated that enhanced expression of STC1 promoted tumor growth and metastasis in mice. Collectively, the results indicated that STC1 may serve an oncogenic role in hypoxic GC via dysregulating Bcl‑2, indicating that STC1 may be a potential therapeutic target in the treatment of GC.

Sakata J, Sasayama T, Tanaka K, et al.
MicroRNA regulating stanniocalcin-1 is a metastasis and dissemination promoting factor in glioblastoma.
J Neurooncol. 2019; 142(2):241-251 [PubMed] Related Publications
BACKGROUND: MicroRNAs (miRs) regulate many biological processes, such as invasion, angiogenesis, and metastasis. Glioblastoma (GBM) patients with metastasis/metastatic dissemination have a very poor prognosis; therefore, inhibiting metastasis/metastatic dissemination has become an important therapeutic strategy for GBM treatment.
METHODS: Using 76 GBM tissues, we examined the expression levels of 23 GBM-related miRs and compared the miRs' expression levels between GBMs with metastasis/metastatic dissemination and GBMs without metastasis/metastatic dissemination. Using the bioinformatics web site, we searched the target genes of miRs. To analyze the function of target gene, several biological assays and survival analysis by the Kaplan-Meier method were performed.
RESULTS: We found that eight miRs were significantly decreased in GBM with metastasis/metastatic dissemination. By the bioinformatics analysis, we identified stanniocalcin-1 (STC1) as the most probable target gene against the combination of these miRs. Four miRs (miR-29B, miR-34a, miR-101, and miR-137) have predictive binding sites in STC1 mRNA, and mRNA expression of STC1 was downregulated by mimics of these miRs. Also, mimics of these miRs and knockdown of STC1 by siRNA suppressed invasion in GBM cells. GBM with metastasis/metastatic dissemination had significantly higher levels of STC1 than GBM without metastasis/metastatic dissemination. Finally, Kaplan-Meier analysis demonstrated that GBMs with high STC1 level had significantly shorter survival than GBMs with low STC1 level.
CONCLUSIONS: STC1 may be a novel metastasis/metastatic dissemination promoting factor regulated by several miRs in GBM. Because STC1 is a secreted glycoprotein and functions via the autocrine/paracrine signals, inhibiting STC1 signal may become a novel therapeutic strategy for GBM.

Lin CL, Tsai ML, Lin CY, et al.
HDAC1 and HDAC2 Double Knockout Triggers Cell Apoptosis in Advanced Thyroid Cancer.
Int J Mol Sci. 2019; 20(2) [PubMed] Free Access to Full Article Related Publications
Anaplastic thyroid carcinoma (ATC) and squamous thyroid carcinoma (STC) are both rare and advanced thyroid malignancies with a very poor prognosis and an average median survival time of 5 months and less than 20% of affected patients are alive 1 year after diagnosis. The clinical management of both ATC and STC is very similar because they are not particularly responsive to radiotherapy and chemotherapy. This inspired us to explore a novel and effective clinically approved therapy for ATC treatment. Histone deacetylase inhibitor (HDACi) drugs are recently FDA-approved drug for malignancies, especially for blood cell cancers. Therefore, we investigated whether an HDACi drug acts as an effective anticancer drug for advanced thyroid cancers. Cell viability analysis of panobinostat treatment demonstrated a significant IC50 of 0.075 µM on SW579 STC cells. In addition, panobinostat exposure activated histone acetylation and triggered cell death mainly through cell cycle arrest and apoptosis-related protein activation. Using CRISPR/Cas9 to knock out

Huang S, Chi Y, Qin Y, et al.
CAPG enhances breast cancer metastasis by competing with PRMT5 to modulate STC-1 transcription.
Theranostics. 2018; 8(9):2549-2564 [PubMed] Free Access to Full Article Related Publications
Macrophage-capping protein (CAPG) has been shown to promote cancer cell metastasis, although the mechanism remains poorly understood.

Li Y, He ZC, Zhang XN, et al.
Stanniocalcin-1 augments stem-like traits of glioblastoma cells through binding and activating NOTCH1.
Cancer Lett. 2018; 416:66-74 [PubMed] Related Publications
Glioblastoma (GBM) is a fatal tumor and comprises heterogeneous cells in which a subpopulation with stem cell-like properties is included. Cancer cells with stem cell-like properties account for tumor initiation, drug resistance and recurrence. To identify and characterize specific factors in regulating stem-like traits is critical for GBM therapeutic. Here, we showed that Stanniocalcin-1 (STC1), a secretory glycoprotein, functions as a novel stimulator for stem-like traits of GBM cells. We found STC1 was prominently expressed in glioma spheres which are mainly comprised of glioma stem-like cells. The stem-like traits of GBM cells, as determined by the expression of stem cell markers, tumor-sphere formation efficiency and colony-forming ability, were enhanced by STC1 overexpression and inhibited by STC1 knockdown. Furthermore, introduction of STC1 enhanced tumorigenesis in vivo while knockdown of STC1 showed reverse effect. Finally, we demonstrated that STC1 interacted with the extracellular domain of NOTCH1 to activate NOTCH1-SOX2 signaling pathway, by which STC1 augmented the stem-like traits of GBM cells. Taken together, our data herein indicate that STC1 is a novel non-canonical NOTCH ligand and acts as a crucial regulator of stemness in GBM.

Chan KK, Leung CO, Wong CC, et al.
Secretory Stanniocalcin 1 promotes metastasis of hepatocellular carcinoma through activation of JNK signaling pathway.
Cancer Lett. 2017; 403:330-338 [PubMed] Related Publications
The hypoxic microenvironment is well-characterized in hepatocellular carcinoma (HCC). Delineation of hypoxia-responsive events is an integral part to understand the pathogenesis of HCC. We studied the functional role and clinical relevance of Stanniocalcin 1 (STC1), a hypoxia-induced molecular target, in HCC. In our clinical cohort, STC1 transcript was up-regulated in HCC tumor tissues. Moreover, STC1 protein was detected in the sera of HCC patients. A higher serum STC1 level was correlated with larger tumor size and poorer 5-year disease-free survival. Functionally, recombinant STC1 protein (rhSTC1) promoted cell migration and cell invasion in vitro; and the effect was abolished by co-treatment of anti-STC1 neutralizing antibody. By in vivo mouse model, silencing of STC1 in HCC cells downregulated secretory STC1 level and suppressed lung metastasis. Furthermore, we found that rhSTC1 activated the JNK pathway, as evidenced by altered expression of the key molecular targets pJNK and p-c-Jun. The functional effects conferred by rhSTC1 were abrogated by co-treatment of JNK inhibitor. In summary, secretory STC1 enhances metastatic potential of HCC via JNK signaling. It potentially serves as a prognostic serum biomarker and a therapeutic target for HCC.

Lu M, Song Y, Fu W, et al.
MicroRNA and target mRNA selection through invasion and cytotoxicity cell modeling and bioinformatics approaches in esophageal squamous cell carcinoma.
Oncol Rep. 2017; 38(2):1181-1189 [PubMed] Related Publications
This study analyzed microRNA (miRNA) and mRNA expression profiles and investigated the biological characteristics of ESCC by using invasion and cytotoxicity cell models. miRNA profiles were evaluated through miRNA microarray. Transwell chamber and nedaplatin (NDP) were used to construct invasion and cytotoxicity cell models. Invasion Transwell and cytotoxicity assays were performed to examine the invasiveness and proliferation in the cell models. Functional miRNAs were selected from dysregulated miRNAs through qRT-PCR. Biometric Research Program (BRB)-array tools, Cytoscape plugins, and DAVID were utilized to find potential mRNAs targeted by these two miRNAs between ESCC and paired normal adjacent tissues. Our microarray obtained 11 dysregulated miRNAs expressed in three paired ESCC samples from Kazakhs (ethnicity in Northwestern China). qRT-PCR demonstrated the miRNA expression in the invasion and cytotoxicity cell models. miR‑652-5p and miR‑21‑5p exhibited a consistent expression level in the microarray and cell models. Bioinformatics revealed that the potential targets of PLD1, MSH2, STC1, and DSG1 might be involved in ESCC invasion and proliferation. Cell models with bioinformatics approaches may help distinguish functional genes. miR‑652-5p, miR‑21‑5p, and their potential target genes may participate in ESCC development and metastasis.

Zandberga E, Zayakin P, Ābols A, et al.
Depletion of carbonic anhydrase IX abrogates hypoxia-induced overexpression of stanniocalcin-1 in triple negative breast cancer cells.
Cancer Biol Ther. 2017; 18(8):596-605 [PubMed] Free Access to Full Article Related Publications
Carbonic anhydrase IX (CAIX) is a pH-regulating enzyme that plays a key role in maintaining an alkaline intracellular pH under hypoxic conditions. It is overexpressed in a variety of solid cancers, including breast cancer (BC), and has been implicated in the migration, invasion and stemness of breast cancer cells. Therefore, CAIX recently emerged as a novel therapeutic target for the treatment of BC. To gain an insight into the mechanism of action of CAIX inhibitors, we investigated the impact of CAIX knock-down on the transcriptional response to hypoxia in 2 BC cell lines - MCF7 and MDA-MB-231, by performing a global gene expression analysis. This showed that CAIX knock-down had a relatively minor effect on the global transcriptional response to hypoxia, however it blocked hypoxia-induced upregulation of stanniocalcin-1 (STC1), a secreted glycoprotein that has been shown to promote tumor progression and metastasis in BC. Kaplan-Meier survival analysis showed that high STC1 expression is significantly associated with poor survival in patients with basal-type breast cancer but not luminal A and HER2+ subtypes. Moreover, the association was particularly high in a subgroup of basal-type BC patients with TP53 mutations thus revealing a putative cooperation of STC1 with mutated TP53 in generating highly aggressive BC subgroup. Taken together, these findings show that CAIX inhibitors at least partially act through blocking STC1 induction in BC cells and reveal a subgroup of BC patients, who potentially would benefit most from the treatment with CAIX inhibitors.

Pan X, Jiang B, Liu J, et al.
STC1 promotes cell apoptosis via NF-κB phospho-P65 Ser536 in cervical cancer cells.
Oncotarget. 2017; 8(28):46249-46261 [PubMed] Free Access to Full Article Related Publications
Stanniocalin-1 (STC1) is a secreted glycoprotein hormone and involved in various types of human malignancies. Our previous studies revealed that STC1 inhibited cell proliferation and invasion of cervical cancer cells through NF-κB P65 activation, but the mechanism is poorly understood. In our studies, we found overexpression of STC1 promoted cell apoptosis while silencing of STC1 promoted cell growth of cervical cancer. Phospho-protein profiling and Western blotting results showed the expression of NF-κB related phosphorylation sites including NF-κB P65 (Ser536), IκBα, IKKβ, PI3K, and AKT was altered in STC1-overexpressed cervical cancer cells. Moreover, PI3K inhibitor LY294002, AKT-shRNA and IκBα-shRNA could decrease the protein content of phospho-P65 (Ser536), phospho-IκBα, phospho-AKT and phospho-IKKβ while increasing the level of P65 compared to STC1 overexpression groups in cervical cancer cells. Also, PI3K inhibitor LY294002, AKT-shRNA and IκBα-shRNA elevated the percentage of apoptosis and suppressed the G1/S transition in those cells. Additionally, STC1 level was decreased in cervical cancer, especial in stage II and III. The results of immunohistochemistry for the cervical cancer microarray showed that a lower level of STC1, phospho-PI3K and P65 protein expression in tumor tissues than that in normal tissues, and a higher level of phospho-P65 protein expression in tumor tissues, which is consistent with the results of the Western blotting. These data demonstrated that STC1 can promote cell apoptosis via NF-κB phospho-P65 (Ser536) by PI3K/AKT, IκBα and IKK signaling in cervical cancer cells. Our results offer the first mechanism that explains the link between STC1 and cell apoptosis in cervical cancer.

Bai Y, Xiao Y, Dai Y, et al.
Stanniocalcin 1 promotes cell proliferation via cyclin E1/cyclin‑dependent kinase 2 in human prostate carcinoma.
Oncol Rep. 2017; 37(4):2465-2471 [PubMed] Related Publications
Stanniocalcin 1 (STC1) is a glycoprotein hormone that is involved in calcium/phosphate homeostasis. Increasing evidence suggests that STC1 is involved in carcinogenesis; however, few studies have defined the mechanisms and functional roles of STC1 activity in prostate carcinogenesis. In the present study, MTT, flow cytometry and colony formation assays, and small interfering RNA (siRNA) and overexpression in multiple cell lines were used to investigate the function of STC1 in prostate carcinoma in vivo and in vivo. Knockdown of endogenous STC1 using a siRNA decreased the proliferation of DU145 and LNCaP2 cells. These results were consistent with the changes in the protein levels of cyclin E1 and cyclin‑dependent kinase 2. By contrast, increased expression of STC1 in RWPE-1 cells led to increased cell proliferation, suggesting that STC1 promotes prostate carcinoma cell proliferation. In summary, the present study investigated the impact of STC1 on the proliferation and growth of prostate cancer in an effort to evaluate STC1 as a predictive biomarker and as a potential target for therapy.

Regazzo D, Losa M, Albiger NM, et al.
The GIP/GIPR axis is functionally linked to GH-secretion increase in a significant proportion of
Eur J Endocrinol. 2017; 176(5):543-553 [PubMed] Related Publications
OBJECTIVE: Glucose-dependent insulinotropic polypeptide receptor (
DESIGN AND METHODS: This study was aimed at linking the GIP/GIPR pathway to GH secretion in 25 somatotropinomas-derived primary cultures and correlating molecular with clinical features in acromegalic patients. Given the impairment of the GIP/GIPR axis in acromegaly, an additional aim was to assess the effect of GH/IGF-1 stimulation on GIP expression in the enteroendocrine cell line STC-1.
RESULTS: Nearly 80% of
CONCLUSIONS: We demonstrate that

Zuo X, Xu W, Xu M, et al.
Metastasis regulation by PPARD expression in cancer cells.
JCI Insight. 2017; 2(1):e91419 [PubMed] Free Access to Full Article Related Publications
Peroxisome proliferator-activated receptor-δ (PPARD) is upregulated in many major human cancers, but the role that its expression in cancer cells has in metastasis remains poorly understood. Here, we show that specific PPARD downregulation or genetic deletion of PPARD in cancer cells significantly repressed metastasis in various cancer models in vivo. Mechanistically, PPARD promoted angiogenesis via interleukin 8 in vivo and in vitro. Analysis of transcriptome profiling of HCT116 colon cancer cells with or without genetic deletion of PPARD and gene expression patterns in The Cancer Genome Atlas colorectal adenocarcinoma database identified novel pro-metastatic genes (GJA1, VIM, SPARC, STC1, SNCG) as PPARD targets. PPARD expression in cancer cells drastically affected epithelial-mesenchymal transition, migration, and invasion, further underscoring its necessity for metastasis. Clinically, high PPARD expression in various major human cancers (e.g., colorectal, lung, breast) was associated with significantly reduced metastasis-free survival. Our results demonstrate that PPARD, a druggable protein, is an important molecular target in metastatic cancer.

Wang H, Fu Z, Dai C, et al.
LncRNAs expression profiling in normal ovary, benign ovarian cyst and malignant epithelial ovarian cancer.
Sci Rep. 2016; 6:38983 [PubMed] Free Access to Full Article Related Publications
Long noncoding RNA (lncRNA) has been recognized as a regulator of gene expression, and the dysregulation of lncRNAs is involved in the progression of many types of cancer, including epithelial ovarian cancer (EOC). To explore the potential roles of lncRNAs in EOC, we performed lncRNA and mRNA microarray profiling in malignant EOC, benign ovarian cyst and healthy control tissues. In this study, 663 transcripts of lncRNAs were found to be differentially expressed in malignant EOC compared with benign and normal control tissues. We also selected 18 altered lncRNAs to confirm the validity of the microarray analysis using quantitative real-time PCR (qPCR). Pathway and Gene Ontology (GO) analyses demonstrated that these altered transcripts were involved in multiple biological processes, especially the cell cycle. Furthermore, Series Test of Cluster (STC) and lncRNA-mRNA co-expression network analyses were conducted to predict lncRNA expression trends and the potential target genes of lncRNAs. We also determined that two antisense lncRNAs (RP11-597D13.9 and ADAMTS9-AS1) were associated with their nearby coding genes (FAM198B, ADAMTS9), which participated in cancer progression. This study offers helpful information to understand the initiation and development mechanisms of EOC.

Han J, Jeon M, Shin I, Kim S
Elevated STC‑1 augments the invasiveness of triple‑negative breast cancer cells through activation of the JNK/c‑Jun signaling pathway.
Oncol Rep. 2016; 36(3):1764-71 [PubMed] Related Publications
Stanniocalcin‑1 (STC‑1), a secreted glycoprotein, is highly expressed in a variety of human malignancies. However, the role of STC‑1 has not been fully elucidated in breast cancer cells. Here, we investigated whether STC‑1 acts as a prognostic factor in triple‑negative breast cancer (TNBC) patients, and we explored the cellular mechanism in breast cancer cells. The level of STC‑1 expression was directly associated with the relapse‑free and overall survival of basal‑type breast cancer patients. Breast cancer patients with a high level of STC‑1 had poor prognosis. In addition, our results showed that the level of STC‑1 expression was markedly higher in TNBC than in non‑TNBC cells. Invasiveness of the TNBC cells was also significantly increased in response to recombinant human STC‑1 treatment. In contrast, the invaded cell numbers were completely decreased by STC‑1 siRNA overexpression in the Hs578T and MDA‑MB‑231 TNBC cells. Our results showed that the phosphorylation of c‑Jun N‑terminal protein kinase (JNK) and c‑Jun was increased after STC‑1 treatment but not the phosphorylation of ERK and p38 MAPKs in the Hs578T and MDA‑MB‑231 TNBC cells. Furthermore, expression of one invasion‑related gene MMP‑9, was increased by STC‑1 treatment. STC‑1‑induced MMP‑9 expression was suppressed by SP600125 (a JNK inhibitor) in the Hs578T cells. STC‑1‑induced cell invasiveness was also inhibited by SP600125. Taken together, we demonstrated that aberrant STC‑1 expression is associated with poor prognosis and stimulates the invasiveness of TNBC cells through the JNK/c‑Jun‑dependent signaling pathway.

Labourier E
Utility and cost-effectiveness of molecular testing in thyroid nodules with indeterminate cytology.
Clin Endocrinol (Oxf). 2016; 85(4):624-31 [PubMed] Related Publications
CONTEXT: Molecular testing on biopsies from thyroid nodules with indeterminate cytology can improve patient management by preventing unnecessary surgeries on benign nodules.
OBJECTIVE: The aim of the study was to determine the health outcome benefits and cost-effectiveness of molecular testing in nodules with AUS/FLUS or FN/SFN cytology.
DESIGN: The initial diagnosis and treatment of a hypothetical cohort of adult U.S. patients with solitary thyroid nodules ≥1 cm was simulated by decision analytic modelling using Medicare cost estimates for three management strategies, standard of care without molecular testing (StC), gene expression classifier (GEC) and mutation and miRNA testing (MMT).
RESULTS: Gene expression classifier decreased the rate of unnecessary surgeries by 32% relative to StC, yielding incremental costs of $1008 per patient or $5070 per unnecessary surgery avoided. MMT decreased the surgery rate by 67%, yielding incremental savings of -$1384 per patient or -$3170 per unnecessary surgery avoided. Results remained robust in deterministic sensitivity analyses; MMT was dominant for every variable tested. Independent of cancer prevalence, MMT yielded 52% fewer unnecessary surgeries relative to GEC #bib70% fewer two-stage thyroidectomies and correctly identified 70% more benign nodules. Test specificity had to be >68% for molecular testing to be cost-effective and decrease by >50% the rate of unnecessary surgeries performed on benign nodules.
CONCLUSIONS: Molecular testing with high benign diagnostic yield can generate both positive health outcomes (less surgeries) and positive economic outputs (cost savings). These results are consistent with previously reported cost-utility data and provide valuable insights for informed decision-making by patients, physicians and payers.

Cheung PF, Cheung TT, Yip CW, et al.
Hepatic cancer stem cell marker granulin-epithelin precursor and β-catenin expression associate with recurrence in hepatocellular carcinoma.
Oncotarget. 2016; 7(16):21644-57 [PubMed] Free Access to Full Article Related Publications
Granulin-epithelin precursor (GEP) has been demonstrated to confer enhanced cancer stem-like cell properties in hepatocellular carcinoma (HCC) cell line models in our previous studies. Here, we aimed to examine the GEP-expressing cells in relation to the stem cell related molecules and stem-like cell properties in the prospective HCC clinical cohort. GEP protein levels were significantly higher in HCCs than the paralleled non-tumor liver tissues, and associated with venous infiltration. GEPhigh cells isolated from clinical HCC samples exhibited higher levels of stem cell marker CD133, pluripotency-associated signaling molecules β-catenin, Oct4, SOX2, Nanog, and chemodrug transporter ABCB5. In addition, GEPhigh cells possessed preferential ability to form colonies and spheroids, and enhanced in vivo tumor-initiating ability while their xenografts were able to be serially subpassaged into secondary mouse recipients. Expression levels of GEP and pluripotency-associated genes were further examined in the retrospective HCC cohort and demonstrated significant correlation of GEP with β-catenin. Notably, HCC patients with high GEP and β-catenin levels demonstrated poor recurrence-free survival. In summary, GEP-positive HCC cells directly isolated from clinical specimens showed β-catenin elevation and cancer stem-like cell properties.

Sundaresan S, Kang AJ, Hayes MM, et al.
Deletion of
Gut. 2017; 66(6):1012-1021 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gastric carcinoids are slow growing neuroendocrine tumours arising from enterochromaffin-like (ECL) cells in the corpus of stomach. Although most of these tumours arise in the setting of gastric atrophy and hypergastrinemia, it is not understood what genetic background predisposes development of these ECL derived tumours. Moreover, diffuse microcarcinoids in the mucosa can lead to a field effect and limit successful endoscopic removal.
OBJECTIVE: To define the genetic background that creates a permissive environment for gastric carcinoids using transgenic mouse lines.
DESIGN: The multiple endocrine neoplasia 1 gene locus (Men1) was deleted using Cre recombinase expressed from the Villin promoter (Villin-Cre) and was placed on a somatostatin null genetic background. These transgenic mice received omeprazole-laced chow for 6 months. The direct effect of gastrin and the gastrin receptor antagonist YM022 on expression and phosphorylation of the cyclin inhibitor p27
RESULTS: The combination of conditional Men1 deletion in the absence of somatostatin led to the development of gastric carcinoids within 2 years. Suppression of acid secretion by omeprazole accelerated the timeline of carcinoid development to 6 months in the absence of significant parietal cell atrophy. Carcinoids were associated with hypergastrinemia, and correlated with increased Cckbr expression and nuclear export of p27
CONCLUSIONS: Gastric carcinoids require threshold levels of hypergastrinemia, which modulates p27

Park WY, Hong BJ, Lee J, et al.
H3K27 Demethylase JMJD3 Employs the NF-κB and BMP Signaling Pathways to Modulate the Tumor Microenvironment and Promote Melanoma Progression and Metastasis.
Cancer Res. 2016; 76(1):161-70 [PubMed] Related Publications
Histone methylation is a key epigenetic mark that regulates gene expression. Recently, aberrant histone methylation patterns caused by deregulated histone demethylases have been associated with carcinogenesis. However, the role of histone demethylases, particularly the histone H3 lysine 27 (H3K27) demethylase JMJD3, remains largely uncharacterized in melanoma. Here, we used human melanoma cell lines and a mouse xenograft model to demonstrate a requirement for JMJD3 in melanoma growth and metastasis. Notably, in contrast with previous reports examining T-cell acute lymphoblastic leukemia and hepatoma cells, JMJD3 did not alter the general proliferation rate of melanoma cells in vitro. However, JMJD3 conferred melanoma cells with several malignant features such as enhanced clonogenicity, self-renewal, and transendothelial migration. In addition, JMJD3 enabled melanoma cells not only to create a favorable tumor microenvironment by promoting angiogenesis and macrophage recruitment, but also to activate protumorigenic PI3K signaling upon interaction with stromal components. Mechanistic investigations demonstrated that JMJD3 transcriptionally upregulated several targets of NF-κB and BMP signaling, including stanniocalcin 1 (STC1) and chemokine (C-C motif) ligand 2 (CCL2), which functioned as downstream effectors of JMJD3 in self-renewal and macrophage recruitment, respectively. Furthermore, JMJD3 expression was elevated and positively correlated with that of STC1 and CCL2 in human malignant melanoma. Moreover, we found that BMP4, another JMJD3 target gene, regulated JMJD3 expression via a positive feedback mechanism. Our findings reveal a novel epigenetic mechanism by which JMJD3 promotes melanoma progression and metastasis, and suggest JMJD3 as a potential target for melanoma treatment.

Abaza HM, Elmougy MI, El Maraghy HM, Mahmoud HM
Stanniocalcin1 gene expression in patients with acute leukemia: impact on response to therapy and disease outcome.
Int J Lab Hematol. 2016; 38(1):81-9 [PubMed] Related Publications
INTRODUCTION: Stanniocalcin1 (STC1) is a hormone that regulates cell growth and survival; this study aimed to evaluate the STC1 gene expression in patients with acute leukemia and assess its prognostic significance.
METHODS: Seventy-six patients with acute leukemia were enrolled for determination of mRNA STC1 by real-time quantitative polymerase chain reaction at diagnosis and at day 28.
RESULTS: Median STC1 gene expression was 16.2 and 4.43 in patients with acute myeloid leukemia and 9.67 and 2.37 in patients with acute lymphoblastic leukemia on days 0 and 28, respectively. A cutoff level for STC1 gene expression was established subdividing patients into high- and low-STC1 gene expression groups. Median STC1 gene expression at days 0 and 28 was significantly higher among patients who were nonresponders to therapy than among those who were therapy responders in both groups. Patients achieving complete remission had significantly lower baseline STC1 gene expression than those in relapse. High STC1 gene expression was associated with shorter overall and disease-free survival times.
CONCLUSION: STC1 gene expression at diagnosis might be a useful prognostic marker for clinical outcome and monitoring therapeutic response in patients with acute leukemia.

Dai D, Wang Q, Li X, et al.
Klotho inhibits human follicular thyroid cancer cell growth and promotes apoptosis through regulation of the expression of stanniocalcin-1.
Oncol Rep. 2016; 35(1):552-8 [PubMed] Related Publications
The new anti-aging gene Klotho has been identified as a multi-functional humoral factor which influences multiple biological processes, including tumor progression. Although ample evidence indicates that Klotho plays important roles in cervical, lung and breast cancer, the role and mechanism of Klotho in thyroid cancer are still unclear. The present study aimed to investigate the effects and mechanisms of Klotho in human thyroid cancer cell lines FTC133 and FTC238. Klotho overexpression markedly reduced thyroid cancer FTC133 and FTC238 cell proliferation and enhanced apoptosis, whereas, Klotho silencing in the FTC133 and FTC238 cells increased cell growth. Moreover, soluble human KL1 (sKL) and Klotho overexpression had a similar effect on FTC133 and FTC238 cell growth. A high level of Klotho was also found to be associated with a low level of stanniocalcin 1 (STC1) in both the FTC133 and FTC238 cell lines. STC1 silencing significantly inhibited thyroid cancer cell proliferation, whereas recombinant human STC1 (hSTC1) markedly enhanced cell proliferation. In addition, our study demonstrated that hSTC1 treatment attenuated Klotho-induced inhibition of cell proliferation and promotion of apoptosis. Our data revealed the existence of a moderating effect between Klotho and STC1, where Klotho may inhibit thyroid tumor progression by inhibiting the tumor marker level of STC1.

Yeung BH, Shek FH, Lee NP, Wong CK
Stanniocalcin-1 Reduces Tumor Size in Human Hepatocellular Carcinoma.
PLoS One. 2015; 10(10):e0139977 [PubMed] Free Access to Full Article Related Publications
Growing evidence has revealed high expression levels of stanniocalcin-1 (STC1) in different types of human cancers. Numerous experimental studies using cancer cell lines demonstrated the involvement of STC1 in inflammatory and apoptotic processes; however the role of STC1 in carcinogenesis remains elusive. Hepatocellular carcinoma (HCC) an exemplified model of inflammation-related cancer, represents a paradigm of studying the association between STC1 and tumor development. Therefore, we conducted a statistical analysis on the expression levels of STC1 using clinicopathological data from 216 HCC patients. We found that STC1 was upregulated in the tumor tissues and its expression levels was positively correlated with the levels of interleukin (IL)-6 and IL-8. Intriguingly tumors with greater expression levels of STC1 (tumor/normal ≥ 2) were significantly smaller than the lower level (tumor/normal<2) samples (p = 0.008). A pharmacological approach was implemented to reveal the functional correlation between STC1 and the ILs in the HCC cell-lines. IL-6 and IL-8 treatment of Hep3B cells induced STC1 expression. Lentiviral-based STC1 overexpression in Hep3B and MHCC-97L cells however showed inhibitory action on the pro-migratory effects of IL-6 and IL-8 and reduced size of tumor spheroids. The inhibitory effect of STC1 on tumor growth was confirmed in vivo using the stable STC1-overexpressing 97L cells on a mouse xenograft model. Genetic analysis of the xenografts derived from the STC1-overexpressing 97L cells, showed upregulation of the pro-apoptotic genes interleukin-12 and NOD-like receptor family, pyrin domain-containing 3. Collectively, the anti-inflammatory and pro-apoptotic functions of STC1 were suggested to relate its inhibitory effect on the growth of HCC cells. This study supports the notion that STC1 may be a potential therapeutic target for inflammatory tumors in HCC patients.

Bollard J, Massoma P, Vercherat C, et al.
The axon guidance molecule semaphorin 3F is a negative regulator of tumor progression and proliferation in ileal neuroendocrine tumors.
Oncotarget. 2015; 6(34):36731-45 [PubMed] Free Access to Full Article Related Publications
Gastro-intestinal neuroendocrine tumors (GI-NETs) are rare neoplasms, frequently metastatic, raising difficult clinical and therapeutic challenges due to a poor knowledge of their biology. As neuroendocrine cells express both epithelial and neural cell markers, we studied the possible involvement in GI-NETs of axon guidance molecules, which have been shown to decrease tumor cell proliferation and metastatic dissemination in several tumor types. We focused on the role of Semaphorin 3F (SEMA3F) in ileal NETs, one of the most frequent subtypes of GI-NETs.SEMA3F expression was detected in normal neuroendocrine cells but was lost in most of human primary tumors and all their metastases. SEMA3F loss of expression was associated with promoter gene methylation. After increasing endogenous SEMA3F levels through stable transfection, enteroendocrine cell lines STC-1 and GluTag showed a reduced proliferation rate in vitro. In two different xenograft mouse models, SEMA3F-overexpressing cells exhibited a reduced ability to form tumors and a hampered liver dissemination potential in vivo. This resulted, at least in part, from the inhibition of mTOR and MAPK signaling pathways.This study demonstrates an anti-tumoral role of SEMA3F in ileal NETs. We thus suggest that SEMA3F and/or its cellular signaling pathway could represent a target for ileal NET therapy.

Ma X, Gu L, Li H, et al.
Hypoxia-induced overexpression of stanniocalcin-1 is associated with the metastasis of early stage clear cell renal cell carcinoma.
J Transl Med. 2015; 13:56 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Although metastasis of clear cell renal cell carcinoma (ccRCC) is predominantly observed in late stage tumors, early stage metastasis of ccRCC can also be found with indefinite molecular mechanism, leading to inappropriate clinical decisions and poor prognosis. Stanniocalcin-1 (STC1) is a glycoprotein hormone involved in calcium/phosphate homeostasis, which regulates various cellular processes in normal development and tumorigenesis. This study aimed to investigate the role and mechanism of regulation of STC1 in the metastasis of early stage ccRCC.
METHODS: STC1 mRNA and protein expression was determined in ccRCC surgical specimens, RCC cell lines, and human kidney tubule epithelial cell line HKC by real-time polymerase chain reaction (RT-PCR) and western blotting. Immunohistochemistry staining (IHC) and immunofluorescence were also used to examine the expression and localization of STC1 in ccRCC tissues and cancer cells. Knockdown and overexpression studies were conducted in vitro in RCC cell lines using small interfering RNAs (siRNA) and lentiviral-mediated gene delivery to evaluate the role of STC1 in cell proliferation, anchorage-dependent and independent growth, cell cycle control, and migration and invasion.
RESULTS: STC1 mRNA and protein expression were significantly up-regulated in tumors when compared with non-tumor tissues, with the greatest increase in expression observed in metastatic tissues. Clinicopathological analysis revealed that STC1 mRNA expression was associated with Fuhrman tumor grade (P = 0.008) and overall Tumor Node Metastasis (TNM) staging (P = 0.018). STC1 expression was elevated in T1 stage metastatic tumors when compared with localized tumors, and was positively correlated with average tumor diameter. Silencing of STC1 expression by Caki-1 and A498 resulted in the inhibition of cell proliferation, migration, and invasion, meanwhile down-regulation of STC1 impaired epithelial-mesenchymal transition (EMT) of ccRCC cell lines. Overexpression of STC1 in Caki-2 enhanced cell growth and proliferation but not migration and invasion. Further investigation identified hypoxia and HIF-1α as candidate regulators of STC1 expression.
CONCLUSIONS: Our findings demonstrate a role for STC1 in metastasis of early stage ccRCC and suggest that STC1 may be a biomarker of potential value both for the prognosis of this disease and for guiding clinical decisions regarding surgical strategies and adjuvant treatment.

Hayase S, Sasaki Y, Matsubara T, et al.
Expression of stanniocalcin 1 in thyroid side population cells and thyroid cancer cells.
Thyroid. 2015; 25(4):425-36 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Mouse thyroid side population (SP) cells consist of a minor population of mouse thyroid cells that may have multipotent thyroid stem cell characteristics. However the nature of thyroid SP cells remains elusive, particularly in relation to thyroid cancer. Stanniocalcin (STC) 1 and 2 are secreted glycoproteins known to regulate serum calcium and phosphate homeostasis. In recent years, the relationship of STC1/2 expression to cancer has been described in various tissues.
METHOD: Microarray analysis was carried out to determine genes up- and down-regulated in thyroid SP cells as compared with non-SP cells. Among genes up-regulated, stanniocalcin 1 (STC1) was chosen for study because of its expression in various thyroid cells by Western blotting and immunohistochemistry.
RESULTS: Gene expression analysis revealed that genes known to be highly expressed in cancer cells and/or involved in cancer invasion/metastasis were markedly up-regulated in SP cells from both intact as well as partial thyroidectomized thyroids. Among these genes, expression of STC1 was found in five human thyroid carcinoma-derived cell lines as revealed by analysis of mRNA and protein, and its expression was inversely correlated with the differentiation status of the cells. Immunohistochemical analysis demonstrated higher expression of STC1 in the thyroid tumor cell line and thyroid tumor tissues from humans and mice.
CONCLUSION: These results suggest that SP cells contain a population of cells that express genes also highly expressed in cancer cells including Stc1, which warrants further study on the role of SP cells and/or STC1 expression in thyroid cancer.

Chang AC, Doherty J, Huschtscha LI, et al.
STC1 expression is associated with tumor growth and metastasis in breast cancer.
Clin Exp Metastasis. 2015; 32(1):15-27 [PubMed] Related Publications
Stanniocalcin-1 (STC1) is a secreted glycoprotein implicated in several pathologies including retinal degeneration, cerebral ischemia, angiogenesis and inflammation. Aberrant STC1 expression has been reported in breast cancer but the significance of this is not clear. High levels of STC1 expression were found in the aggressive 4T1 murine mammary tumor cells and in the MDA-MB-231 human breast cancer line. To investigate its significance, stable clones with STC1 down-regulation using shRNA were generated in both tumor models. The consequences of STC1 down-regulation on cell proliferation, chemotactic invasion, tumor growth and metastasis were assessed. Down-regulation of STC1 in the 4T1 murine mammary tumor cells had a major impact on mammary tumor growth. This observation was replicated in a second tumor model with the MDA-MB-231 human breast cancer line, with a significant reduction in primary tumor formation and a major inhibition of metastasis as well. Interestingly, in both models, proliferation in vitro was not affected. Subsequent microarray gene expression profiling identified 30 genes to be significantly altered by STC1 down-regulation, the majority of which are associated with known hallmarks of carcinogenesis. Furthermore, bioinformatic analysis of breast cancer datasets revealed that high expression of STC1 is associated with poor survival. This is the first study to show definitively that STC1 plays an oncogenic role in breast cancer, and indicates that STC1 could be a potential therapeutic target for treatment of breast cancer patients.

Couderc C, Bollard J, Couté Y, et al.
Mechanisms of local invasion in enteroendocrine tumors: identification of novel candidate cytoskeleton-associated proteins in an experimental mouse model by a proteomic approach and validation in human tumors.
Mol Cell Endocrinol. 2015; 399:154-63 [PubMed] Related Publications
Small-intestinal neuroendocrine tumors (SI-NETs) are defined as locally invasive only after extension to the muscularis propria. To gain further insight into the molecular mechanisms, we applied a proteomic approach to an orthotopic xenograft model to identify candidate proteins evaluable in human SI-NETs. After grafting STC-1 neuroendocrine tumor cells on the caecum of nude mice, comparative proteomic studies were performed between the pre-invasive and the invasive stages, respectively 2 and 8 weeks after grafting. We identified 24 proteins displaying at least a 1.5-fold differential expression between 2 and 8 week-stages. Most were cytoskeleton-associated proteins, among which five showed decreasing expression levels (CRMP2, TCP1ε, TPM2, vimentin, desmin) and two increasing expression levels (14-3-3γ, CK8). Changes for CRMP2, TCP1ε, TPM2 and 14-3-3γ were confirmed in experimental tumors and in a series of 28 human SI-NETs. In conclusion, our results underline the relevance of proteomics to identify novel biomarkers of tissue invasion.

Sun Y, Shen S, Tang H, et al.
miR-429 identified by dynamic transcriptome analysis is a new candidate biomarker for colorectal cancer prognosis.
OMICS. 2014; 18(1):54-64 [PubMed] Free Access to Full Article Related Publications
Colorectal cancer (CRC) is a common malignant gastrointestinal cancer. Efforts for preventive and personalized medicine have intensified in the last decade with attention to novel forms of biomarkers. In the present study, microRNA and genetic analyses were performed in tandem for differential transcriptome profiling between primary tumors with or without nodes or distant metastases. Serial Test Cluster (STC) analysis demonstrated that 20 genes and two microRNAs showed distinctive expression patterns associated with the tumor, node, and metastasis (TNM) stage. The selected target genes were characterized by GO and Pathway analysis. A microRNA-target gene network analysis showed that miR-429 resided in the center of the network, indicating that miR-429 might serve important roles in the development of CRC. Real-time PCR and tissue microarrays showed that miR-429 had a dynamic expression pattern during the CRC progression stage, and was significantly downregulated in stage II and stage III clinical progression. The low expression of miR-429 was correlated with poor prognosis for CRC. Taken together, miR-429 warrant further clinical translation research as a candidate biomarker for CRC prognosis. Additional downstream targets and attendant gene function also need to be discerned to design a sound critical path to personalized medicine for persons susceptible to, or diagnosed with CRC.

Rajaram M, Li J, Egeblad M, Powers RS
System-wide analysis reveals a complex network of tumor-fibroblast interactions involved in tumorigenicity.
PLoS Genet. 2013; 9(9):e1003789 [PubMed] Free Access to Full Article Related Publications
Many fibroblast-secreted proteins promote tumorigenicity, and several factors secreted by cancer cells have in turn been proposed to induce these proteins. It is not clear whether there are single dominant pathways underlying these interactions or whether they involve multiple pathways acting in parallel. Here, we identified 42 fibroblast-secreted factors induced by breast cancer cells using comparative genomic analysis. To determine what fraction was active in promoting tumorigenicity, we chose five representative fibroblast-secreted factors for in vivo analysis. We found that the majority (three out of five) played equally major roles in promoting tumorigenicity, and intriguingly, each one had distinct effects on the tumor microenvironment. Specifically, fibroblast-secreted amphiregulin promoted breast cancer cell survival, whereas the chemokine CCL7 stimulated tumor cell proliferation while CCL2 promoted innate immune cell infiltration and angiogenesis. The other two factors tested had minor (CCL8) or minimally (STC1) significant effects on the ability of fibroblasts to promote tumor growth. The importance of parallel interactions between fibroblasts and cancer cells was tested by simultaneously targeting fibroblast-secreted amphiregulin and the CCL7 receptor on cancer cells, and this was significantly more efficacious than blocking either pathway alone. We further explored the concept of parallel interactions by testing the extent to which induction of critical fibroblast-secreted proteins could be achieved by single, previously identified, factors produced by breast cancer cells. We found that although single factors could induce a subset of genes, even combinations of factors failed to induce the full repertoire of functionally important fibroblast-secreted proteins. Together, these results delineate a complex network of tumor-fibroblast interactions that act in parallel to promote tumorigenicity and suggest that effective anti-stromal therapeutic strategies will need to be multi-targeted.

Gañán-Gómez I, Wei Y, Yang H, et al.
Oncogenic functions of the transcription factor Nrf2.
Free Radic Biol Med. 2013; 65:750-764 [PubMed] Related Publications
Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor that controls the expression of a large pool of antioxidant and cytoprotective genes regulating the cellular response to oxidative and electrophilic stress. Nrf2 is negatively regulated by Kelch-like ECH-associated protein 1 (Keap1) and, upon stimulation by an oxidative or electrophilic insult, is rapidly activated by protein stabilization. Owing to its cytoprotective functions, Nrf2 has been traditionally studied in the field of chemoprevention; however, there is accumulated evidence that Keap1/Nrf2 mutations or unbalanced regulation that leads to overexpression or hyperactivation of Nrf2 may participate in tumorigenesis and be involved in chemoresistance of a wide number of solid cancers and leukemias. In addition to protecting cells from reactive oxygen species, Nrf2 seems to play a direct role in cell growth control and is related to apoptosis-regulating pathways. Moreover, Nrf2 activity is connected with oncogenic kinase pathways, structural proteins, hormonal regulation, other transcription factors, and epigenetic enzymes involved in the pathogenesis of various types of tumors. The aim of this review is to compile and summarize existing knowledge of the oncogenic functions of Nrf2 to provide a solid basis for its potential use as a molecular marker and pharmacological target in cancer.

Guo F, Li Y, Wang J, et al.
Stanniocalcin1 (STC1) Inhibits Cell Proliferation and Invasion of Cervical Cancer Cells.
PLoS One. 2013; 8(1):e53989 [PubMed] Free Access to Full Article Related Publications
STC1 is a glycoprotein hormone involved in calcium/phosphate (Pi) homeostasis. There is mounting evidence that STC1 is tightly associated with the development of cancer. But the function of STC1 in cancer is not fully understood. Here, we found that STC1 is down-regulated in Clinical tissues of cervical cancer compared to the adjacent normal cervical tissues (15 cases). Subsequently, the expression of STC1 was knocked down by RNA interference in cervical cancer CaSki cells and the low expression promoted cell growth, migration and invasion. We also found that STC1 overexpression inhibited cell proliferation and invasion of cervical cancer cells. Moreover, STC1 overexpression sensitized CaSki cells to drugs. Further, we showed that NF-κB p65 protein directly bound to STC1 promoter and activated the expression of STC1 in cervical cancer cells. Thus, these results provided evidence that STC1 inhibited cell proliferation and invasion through NF-κB p65 activation in cervical cancer.

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