Gene Summary

Gene:SLPI; secretory leukocyte peptidase inhibitor
Summary:This gene encodes a secreted inhibitor which protects epithelial tissues from serine proteases. It is found in various secretions including seminal plasma, cervical mucus, and bronchial secretions, and has affinity for trypsin, leukocyte elastase, and cathepsin G. Its inhibitory effect contributes to the immune response by protecting epithelial surfaces from attack by endogenous proteolytic enzymes. This antimicrobial protein has antibacterial, antifungal and antiviral activity. [provided by RefSeq, Nov 2014]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 29 August, 2019


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

Research Indicators

Publications Per Year (1994-2019)
Graph generated 29 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

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: SLPI (cancer-related)

Dabral S, Muecke C, Valasarajan C, et al.
A RASSF1A-HIF1α loop drives Warburg effect in cancer and pulmonary hypertension.
Nat Commun. 2019; 10(1):2130 [PubMed] Free Access to Full Article Related Publications
Hypoxia signaling plays a major role in non-malignant and malignant hyperproliferative diseases. Pulmonary hypertension (PH), a hypoxia-driven vascular disease, is characterized by a glycolytic switch similar to the Warburg effect in cancer. Ras association domain family 1A (RASSF1A) is a scaffold protein that acts as a tumour suppressor. Here we show that hypoxia promotes stabilization of RASSF1A through NOX-1- and protein kinase C- dependent phosphorylation. In parallel, hypoxia inducible factor-1 α (HIF-1α) activates RASSF1A transcription via HIF-binding sites in the RASSF1A promoter region. Vice versa, RASSF1A binds to HIF-1α, blocks its prolyl-hydroxylation and proteasomal degradation, and thus enhances the activation of the glycolytic switch. We find that this mechanism operates in experimental hypoxia-induced PH, which is blocked in RASSF1A knockout mice, in human primary PH vascular cells, and in a subset of human lung cancer cells. We conclude that RASSF1A-HIF-1α forms a feedforward loop driving hypoxia signaling in PH and cancer.

Alp E, Damkaci F, Guven E, Tenniswood M
Starch nanoparticles for delivery of the histone deacetylase inhibitor CG-1521 in breast cancer treatment.
Int J Nanomedicine. 2019; 14:1335-1346 [PubMed] Free Access to Full Article Related Publications
Background: The efficacy of epigenetic drugs, such as histone deacetylase inhibitors, is often diminished by poor aqueous solubility resulting in limited bioavailability and a low therapeutic index. To overcome the suboptimal therapeutic index, we have developed a biocompatible starch nanoparticle formulation of CG-1521, a histone deacetylase inhibitor in preclinical development for hard-to-treat breast cancers, which improves its bioavailability and half-life.
Methods: The physicochemical parameters (size, zeta potential, morphology, loading, and release kinetics) of these nanoparticles (CG-NPs) have been optimized and their cytotoxic and apoptotic capacities measured in MCF-7 breast cancer cell line. The mechanism of action of the encapsulated drug was compared with the free drug at molecular level.
Results: We show that encapsulation of CG-1521 substantially reduces the release rate of drug and provides a significantly enhanced cytotoxic ability of nanoparticles compared with equivalent dose of free CG-1521. CG-NPs induced cell cycle arrest and significant apoptosis in MCF-7 cells in vitro. The biological action of encapsulated drug has the similar impact with free drug on gene expression.
Conclusion: The findings suggest that encapsulation of CG-1521 into starch nanoparticles can improve drug delivery of histone deacetylase inhibitors for breast cancer therapy without interfering with the mechanism of action of the drug.

Gupta P, Gowrishankar S, Swain M
Epidermal growth factor receptor and anaplastic lymphoma kinase mutation in adenocarcinoma lung: Their incidence and correlation with histologic patterns.
Indian J Pathol Microbiol. 2019 Jan-Mar; 62(1):24-30 [PubMed] Related Publications
Introduction: Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutational analysis in adenocarcinoma lung are growing in importance as these tests are essential in guiding the use of targeted therapy. However, the prevalence of these mutations in various populations in India has not been studied. Furthermore, the correlation of histologic pattern with the mutation is not clear.
Materials and Methods: A total of 64 biopsy-proven lung adenocarcinomas were selected. In 51 of these, EGFR mutational analysis was performed using Qiagen EGFR pyrosequencing kit and in 56 cases of these ALK1 immunohistochemistry (IHC) was done using ALK (D5F3) antibody and the Ventana Benchmark
Results: EGFR mutation was positive in 23 cases (45.10%) and positive ALK1 expression by IHC in 12 cases (21.43%). Both mutations were positive in two cases. Both mutations were seen in well-differentiated and moderately differentiated adenocarcinoma, and the expression was highest in tumors with a predominant acinar pattern.
Conclusions: The incidence of both EGFR and ALK1 mutations is higher in the population studied and seem to correlate with a well differentiated, acinar pattern on morphology.

Reyes I, Reyes N, Suriano R, et al.
Gene expression profiling identifies potential molecular markers of papillary thyroid carcinoma.
Cancer Biomark. 2019; 24(1):71-83 [PubMed] Related Publications
BACKGROUND: Thyroid cancer is the most common endocrine malignancy worldwide, with the predominant form papillary thyroid carcinoma (PTC) representing approximately 80% of cases.
OBJECTIVE: This study was addressed to identify potential genes and pathways involved in the pathogenesis of PTC and potential novel biomarkers for this disease.
METHODS: Gene expression profiling was carried out by DNA microarray technology. Validation of microarray data by qRT-PCR, western blot, and enzyme linked immunosorbent assay was also performed in a selected set of genes and gene products, with the potential to be used as diagnostic or prognostic biomarkers, such as those associated with cell adhesion, extracellular matrix (ECM) remodeling and immune/inflammatory response.
RESULTS: In this study we found that upregulation of extracellular activities, such as proteoglycans, ECM-receptor interaction, and cell adhesion molecules, were the most prominent feature of PTC. Significantly over-expressed genes included SDC1 (syndecan 1), SDC4 (syndecan 4), KLK7 (kallikrein-related peptidase 7), KLK10 (kallikrein-related peptidase 10), SLPI (secretory leukocyte peptidase inhibitor), GDF15 (growth/differentiation factor-15), ALOX5 (arachidonate 5-lipoxygenase), SFRP2 (secreted Frizzled-related protein 2), among others. Further, elevated KLK10 levels were detected in patients with PTC. Many of these genes belong to KEGG pathway "Proteoglycans in cancer".
CONCLUSIONS: Using DNA microarray analysis allowed the identification of genes and pathways with known important roles in malignant transformation, and also the discovery of novel genes that may be potential biomarkers for PTC.

Riddell M, Nakayama A, Hikita T, et al.
aPKC controls endothelial growth by modulating c-Myc via FoxO1 DNA-binding ability.
Nat Commun. 2018; 9(1):5357 [PubMed] Free Access to Full Article Related Publications
Strict regulation of proliferation is vital for development, whereas unregulated cell proliferation is a fundamental characteristic of cancer. The polarity protein atypical protein kinase C lambda/iota (aPKCλ) is associated with cell proliferation through unknown mechanisms. In endothelial cells, suppression of aPKCλ impairs proliferation despite hyperactivated mitogenic signaling. Here we show that aPKCλ phosphorylates the DNA binding domain of forkhead box O1 (FoxO1) transcription factor, a gatekeeper of endothelial growth. Although mitogenic signaling excludes FoxO1 from the nucleus, consequently increasing c-Myc abundance and proliferation, aPKCλ controls c-Myc expression via FoxO1/miR-34c signaling without affecting its localization. We find this pathway is strongly activated in the malignant vascular sarcoma, angiosarcoma, and aPKC inhibition reduces c-Myc expression and proliferation of angiosarcoma cells. Moreover, FoxO1 phosphorylation at Ser218 and aPKC expression correlates with poor patient prognosis. Our findings may provide a potential therapeutic strategy for treatment of malignant cancers, like angiosarcoma.

Yokoyama S, Cai Y, Murata M, et al.
A novel pathway of LPS uptake through syndecan-1 leading to pyroptotic cell death.
Elife. 2018; 7 [PubMed] Free Access to Full Article Related Publications
Intracellular lipopolysaccharide (LPS) triggers the non-canonical inflammasome pathway, resulting in pyroptosis of innate immune cells. In addition to its well-known proinflammatory role, LPS can directly cause regression of some tumors, although the underlying mechanism has remained unknown. Here we show that secretoglobin(SCGB)3A2, a small protein predominantly secreted in airways, chaperones LPS to the cytosol through the cell surface receptor syndecan-1; this leads to pyroptotic cell death driven by caspase-11. SCGB3A2 and LPS co-treatment significantly induced pyroptosis of macrophage RAW264.7 cells and decreased cancer cell proliferation in vitro, while SCGB3A2 treatment resulted in reduced progression of xenograft tumors in mice. These data suggest a conserved function for SCGB3A2 in the innate immune system and cancer cells. These findings demonstrate a critical role for SCGB3A2 as an LPS delivery vehicle; they reveal one mechanism whereby LPS enters innate immune cells leading to pyroptosis, and they clarify the direct effect of LPS on cancer cells.

Höglander EK, Nord S, Wedge DC, et al.
Time series analysis of neoadjuvant chemotherapy and bevacizumab-treated breast carcinomas reveals a systemic shift in genomic aberrations.
Genome Med. 2018; 10(1):92 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Chemotherapeutic agents such as anthracyclines and taxanes are commonly used in the neoadjuvant setting. Bevacizumab is an antibody which binds to vascular endothelial growth factor A (VEGFA) and inhibits its receptor interaction, thus obstructing the formation of new blood vessels.
METHODS: A phase II randomized clinical trial of 123 patients with Her2-negative breast cancer was conducted, with patients treated with neoadjuvant chemotherapy (fluorouracil (5FU)/epirubicin/cyclophosphamide (FEC) and taxane), with or without bevacizumab. Serial biopsies were obtained at time of diagnosis, after 12 weeks of treatment with FEC ± bevacizumab, and after 25 weeks of treatment with taxane ± bevacizumab. A time course study was designed to investigate the genomic landscape at the three time points when tumor DNA alterations, tumor percentage, genomic instability, and tumor clonality were assessed. Substantial differences were observed with some tumors changing mainly between diagnosis and at 12 weeks, others between 12 and 25 weeks, and still others changing in both time periods.
RESULTS: In both treatment arms, good responders (GR) and non-responders (NR) displayed significant difference in genomic instability index (GII) at time of diagnosis. In the combination arm, copy number alterations at 25 loci at the time of diagnosis were significantly different between the GR and NR. An inverse aberration pattern was also observed between the two extreme response groups at 6p22-p12 for patients in the combination arm. Signs of subclonal reduction were observed, with some aberrations disappearing and others being retained during treatment. Increase in subclonal amplification was observed at 6p21.1, a locus which contains the VEGFA gene for the protein which are targeted by the study drug bevacizumab. Of the 13 pre-treatment samples that had a gain at VEGFA, 12 were responders. Significant decrease of frequency of subclones carrying gains at 17q21.32-q22 was observed at 12 weeks, with the peak occurring at TMEM100, an ALK1 receptor signaling-dependent gene essential for vasculogenesis. This implies that cells bearing amplifications of VEGFA and TMEM100 are particularly sensitive to this treatment regime.
CONCLUSIONS: Taken together, these results suggest that heterogeneity and subclonal architecture influence the response to targeted treatment in combination with chemotherapy, with possible implications for clinical decision-making and monitoring of treatment efficacy.
TRIAL REGISTRATION: NCT00773695 . Registered 15 October 2008.

Tian X, Guan W, Zhang L, et al.
Physical interaction of STAT1 isoforms with TGF-β receptors leads to functional crosstalk between two signaling pathways in epithelial ovarian cancer.
J Exp Clin Cancer Res. 2018; 37(1):103 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The signal transducer and activator of transcription (STAT) and transforming growth factor-β (TGF-β) signaling pathways play important roles in epithelial ovarian cancer (EOC). However, the mechanism of crosstalk between two pathways is not completely understood.
METHODS: The expression of STAT1 protein was detected by tissue microarray and immunoblotting (IB). The interaction of STAT1 isoforms with TGF-β receptors was confirmed by immunoprecipitation and IB. The effect of TGF-β signaling on STAT1 activation was examined in EOC and non-tumorous HOSEpiC cells treated with TGF-β1 in the presence or absence of the inhibitor of TGF-β type I receptor. The gain-of-function and loss-of-function approaches were applied for detecting the role of STAT1 on EOC cell behaviours.
RESULTS: The high level of STAT1 was observed in patients with high-grade serous EOC. STAT1 expression was higher in ovarian cancer cells than noncancerous cells. TGF-β1 activated the STAT1 pathway by inducing the phosphorylation of STAT1α on S727 residue. The full-length STAT1α and the truncated STAT1β directly interacted with TGF-β receptors (ALK1/ALK5 and TβRII), which was mediated by TGF-β1. STAT1α and STAT1β blocked the activation of the TGF-β1 signaling pathway in EOC cells by reducing Smad2 phosphorylation. STAT1 overexpression induced EOC cell proliferation, migration, and invasion; whereas its inhibition enhanced TGF-β1-induced phospho-Smad2 and suppressed EOC cell proliferation, migration, and invasion.
CONCLUSIONS: Our data unveil a novel insight into the molecular mechanism of crosstalk between the STAT1 and TGF-β signaling pathways, which affected the cancer cell behavior. Suppression of STAT1 may be a potential therapeutic strategy for targeting ovarian cancer.

Hanna DL, Loupakis F, Yang D, et al.
Prognostic Value of ACVRL1 Expression in Metastatic Colorectal Cancer Patients Receiving First-line Chemotherapy With Bevacizumab: Results From the Triplet Plus Bevacizumab (TRIBE) Study.
Clin Colorectal Cancer. 2018; 17(3):e471-e488 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
BACKGROUND: No biomarkers exist to predict benefit from antiangiogenic therapy in metastatic colorectal cancer patients. ACVRL1 (activin receptor like-protein 1) encodes for ALK1, a member of the transforming growth factor-β receptor family, which directs pathologic angiogenesis. We examined the intratumoral expression of ACVRL1 and other angiogenesis pathway-related genes to identify molecular markers in the TRIBE study.
MATERIALS AND METHODS: Of 503 randomized patients, 228 had sufficient tissue for analysis. Formalin-fixed paraffin-embedded specimens were examined for expression of VEGF-A, VEGF-B, VEGF-C, VEGFR1, VEGFR2, ACVRL1, EphB4, and EGFL7 using reverse transcription polymerase chain reaction. A maximal χ
RESULTS: High ACVRL1 expression was associated with superior OS in both treatment arms (FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan]-bevacizumab, 32.7 vs. 13.5 months, hazard ratio [HR], 0.38, P = .023; FOLFIRI [5-fluorouracil, leucovorin, irinotecan]-bevacizumab, 35.1 vs. 22.0 months, HR, 0.36, P = .006) and prolonged PFS (11.7 vs. 5.9 months, multivariate HR, 0.17; P = .001) for patients receiving FOLFOXIRI-bevacizumab on univariate and multivariate analyses. In recursive partitioning analysis, ACVRL1 was the strongest discriminator of the response rate, PFS, and OS in patients receiving FOLFOXIRI-bevacizumab and of OS in patients receiving FOLFIRI-bevacizumab. In silico validation revealed significant associations between ACVRL1 expression, disease recurrence, and 1-year survival (P < .05) among all colorectal cancer stages.
CONCLUSION: ACVRL1 expression could serve as a prognostic biomarker in metastatic colorectal cancer patients receiving chemotherapy and bevacizumab and warrants further evaluation in prospective studies.

Ronchi A, Montella M, Argenzio V, et al.
Diagnosis of anaplastic large cell lymphoma on late peri-implant breast seroma: Management of cytological sample by an integrated approach.
Cytopathology. 2018; 29(3):294-299 [PubMed] Related Publications
INTRODUCTION: Peri-implant breast seroma is a late clinical presentation of reconstructive surgery or augmentation mammoplasty with breast implants. Pre-operative cytological evaluation of the peri-implant breast seroma is a common clinical approach, showing mainly an inflammatory reaction or more rarely a breast implant-associated anaplastic large cell lymphoma. Herein, we reported the role of cytology in the evaluation of peri-implant breast seroma and its critical pre-operative implications.
METHODS: Eight cases of peri-implant breast seroma from files at Luigi Vanvitelli University were identified between January and December 2017. In all cases, seroma was aspirated; cytospins were performed and stained by Papanicolaou stain; finally, in all cases, a cell block was obtained for immunocytochemical evaluation and, in one case, for FISH to detect ALK1-gene translocation.
RESULTS: The median age of patients was 48 years and the mean time between the implant placement and the occurrence of peri-implant breast seroma was 18 months. Microscopic examination showed breast implant-associated anaplastic large cell lymphoma in one case, aspecific inflammatory reaction in six cases and silicon-associated reaction in one case.
CONCLUSIONS: Peri-implant breast seroma may be caused by several pathological conditions with different clinical behaviour. A proper cytological approach to peri-implant breast seroma allows a correct differential diagnosis between inflammatory conditions and breast implant-associated anaplastic large cell lymphoma and an appropriate management of the patient.

Han C, Bellone S, Siegel ER, et al.
A novel multiple biomarker panel for the early detection of high-grade serous ovarian carcinoma.
Gynecol Oncol. 2018; 149(3):585-591 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
INTRODUCTION: Since the majority of patients are diagnosed at an advanced stage, ovarian cancer remains the most lethal gynecologic malignancy. There is no single biomarker with the sensitivity and specificity required for effective cancer screening; therefore, we investigated a panel of novel biomarkers for the early detection of high-grade serous ovarian carcinoma.
METHODS: Twelve serum biomarkers with high differential gene expression and validated antibodies were selected: IL-1Ra, IL-6, Dkk-1, uPA, E-CAD, ErbB2, SLPI, HE4, CA125, LCN2, MSLN, and OPN. They were tested using Simple Plex™, a multi-analyte immunoassay platform, in samples collected from 172 patients who were either healthy, had benign gynecologic pathologies, or had high-grade serous ovarian adenocarcinomas. The receiver operating characteristic (ROC) curve, ROC area under the curve (AUC), and standard error (SE) of the AUC were obtained. Univariate ROC analyses and multivariate ROC analyses with the combination of multiple biomarkers were performed.
RESULTS: The 4-marker panel consisting of CA125, HE4, E-CAD, and IL-6 had the highest ROC AUC. When evaluated for the ability to distinguish early stage ovarian cancer from a non-cancer control, not only did this 4-marker panel (AUC=0.961) performed better than CA 125 alone (AUC=0.851; P=0.0150) and HE4 alone (AUC=0.870; P=0.0220), but also performed significantly better than the 2- marker combination of CA125+HE4 (AUC=0.922; P=0.0278). The 4-marker panel had the highest average sensitivity under the region of its ROC curve corresponding to specificity ranging from 100% down to ~95%.
CONCLUSION: The four-marker panel, CA125, HE4, E-CAD, and IL-6, shows potential in detecting serous ovarian cancer at earlier stages. Additional validation studies using the biomarker combination in ovarian cancer patients are warranted.

Matsushita J, Okamura K, Nakabayashi K, et al.
The DNA methylation profile of liver tumors in C3H mice and identification of differentially methylated regions involved in the regulation of tumorigenic genes.
BMC Cancer. 2018; 18(1):317 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
BACKGROUND: C3H mice have been frequently used in cancer studies as animal models of spontaneous liver tumors and chemically induced hepatocellular carcinoma (HCC). Epigenetic modifications, including DNA methylation, are among pivotal control mechanisms of gene expression leading to carcinogenesis. Although information on somatic mutations in liver tumors of C3H mice is available, epigenetic aspects are yet to be clarified.
METHODS: We performed next generation sequencing-based analysis of DNA methylation and microarray analysis of gene expression to explore genes regulated by DNA methylation in spontaneous liver tumors of C3H mice. Overlaying these data, we selected cancer-related genes whose expressions are inversely correlated with DNA methylation levels in the associated differentially methylated regions (DMRs) located around transcription start sites (TSSs) (promoter DMRs). We further assessed mutuality of the selected genes for expression and DNA methylation in human HCC using the Cancer Genome Atlas (TCGA) database.
RESULTS: We obtained data on genome-wide DNA methylation profiles in the normal and tumor livers of C3H mice. We identified promoter DMRs of genes which are reported to be related to cancer and whose expressions are inversely correlated with the DNA methylation, including Mst1r, Slpi and Extl1. The association between DNA methylation and gene expression was confirmed using a DNA methylation inhibitor 5-aza-2'-deoxycytidine (5-aza-dC) in Hepa1c1c7 cells and Hepa1-6 cells. Overexpression of Mst1r in Hepa1c1c7 cells illuminated a novel downstream pathway via IL-33 upregulation. Database search indicated that gene expressions of Mst1r and Slpi are upregulated and the TSS upstream regions are hypomethylated also in human HCC. These results suggest that DMRs, including those of Mst1r and Slpi, are involved in liver tumorigenesis in C3H mice, and also possibly in human HCC.
CONCLUSIONS: Our study clarified genome wide DNA methylation landscape of C3H mice. The data provide useful information for further epigenetic studies of mice models of HCC. The present study particularly proposed novel DNA methylation-regulated pathways for Mst1r and Slpi, which may be applied not only to mouse HCC but also to human HCC.

Xu S, Yang F, Liu R, et al.
Serum microRNA-139-5p is downregulated in lung cancer patients with lytic bone metastasis.
Oncol Rep. 2018; 39(5):2376-2384 [PubMed] Related Publications
Bone remodeling can be interrupted by tumor cells which leads to an inappropriate balance of osteoblasts and osteoclasts. As the progenitors of osteoblasts, mesenchymal stem cells (MSCs) have been reported to exhibit an abnormal osteogenic differentiation potential in some cancer‑related bone lesions. However, the evidence is very limited in terms of the biological alterations of MSCs in the bone metastasis of non‑small cell lung cancers (NSCLC). We investigated the expression and function of miR‑139‑5p in MSC osteogenic differentiation in vitro in normal and NSCLC-exposed condition. Then, we compared the serum miR‑139‑5p in stage IV lung adenocarcinoma cancer patients with and without lytic bone metastasis. We found that MSCs exhibited a significant increase in miR‑139‑5p expression after exposure to osteogenic differentiation induction medium. However, Notch1, which was confirmed as a target of miR‑139‑5p by luciferase and western blot assays, showed a marked downregulated expression together with its pathway downstream factors during MSC osteogenesis. miR‑139‑5p positively regulated MSC osteogenic differentiation but this effect was abrogated significantly by Notch1 knockdown. After exposure to conditions of lung cancer cells A549 and L9981, MSCs exhibited significant downregulation of miR‑139‑5p expression and early osteogenic marker ALP activity. Furthermore, we demonstrated that the expression of serum miR‑139‑5p from lung adenocarcinoma patients with lytic bone metastasis was significantly lower compared to that in patients with metastases in other organs. The potential roles of miR‑139‑5p as a biomarker and treatment target in monitoring and controlling bone metastasis in lung cancer patients are worthy of being further explored.

Kun-Peng Z, Xiao-Long M, Chun-Lin Z
Overexpressed circPVT1, a potential new circular RNA biomarker, contributes to doxorubicin and cisplatin resistance of osteosarcoma cells by regulating ABCB1.
Int J Biol Sci. 2018; 14(3):321-330 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
Circular RNAs (circRNAs) represent a widespread class of non-coding RNAs generated from back-splicing, with a circular loop structure. Many circRNAs have been reported to play essential roles in cancer development and have the potential to serve as a novel class of biomarkers for clinical diagnosis. However, the role of circRNA in osteosarcoma (OS) remains largely unknown. In the current study, we examined the expression level of circular RNA PVT1 (circPVT1), previously screened and identified the oncogenic role in gastric cancer, in OS and found that circPVT1 was significantly up-regulated in the OS tissues, serums and chemoresistant cell lines, correlated with poor prognosis of OS patients. Besides, ROC curve demonstrated that circPVT1 may be a better diagnostic biomarker than alkaline phosphatase (ALP) in OS with more sensitivity and specificity. In addition, functional assays revealed that circPVT1 knockdown by siRNA could weaken the resistance to doxorubicin and cisplatin of OS cells through decreasing the expression of classical drug resistance-related gene ABCB1. These findings may provide a new insight into the role of circPVT1 as a biomarker for the diagnosis and treatment target of OS.

Fujimoto M, Togashi Y, Matsuzaki I, et al.
A case report of atypical Spitz tumor harboring a novel MLPH-ALK gene fusion with discordant ALK immunohistochemistry results.
Hum Pathol. 2018; 80:99-103 [PubMed] Related Publications
Frequent kinase fusions have been reported in spitzoid neoplasms, approximately 10% of which involve ALK rearrangements. Herein, we report a case of atypical Spitz tumor with a novel MLPH-ALK fusion, which has not been previously reported to contribute to cancer development. The tumor was detected in the right arm of a 40-year-old woman. The novel ALK fusion was identified by a 5'-rapid amplification of cDNA ends-based system optimized for formalin-fixed, paraffin-embedded tissue. Initially, ALK expression was detected by immunohistochemistry using 5A4 antibodies for both sensitive and conventional polymer detection methods. However, the anti-ALK1 antibody, which is commonly used for the diagnosis of ALK-positive anaplastic large cell lymphoma, failed to confirm ALK expression. These results indicated that ALK immunohistochemistry results in ALK-rearranged atypical Spitz tumor may differ based on the type of primary antibody clone, which can be a potential diagnostic pitfall.

Konstantinidis G, Sievers S, Wu YW
Identification of Novel Autophagy Inhibitors via Cell-Based High-Content Screening.
Methods Mol Biol. 2019; 1854:187-195 [PubMed] Related Publications
Autophagy is a fundamental cellular catabolic pathway mediating the recycling of cellular components. Autophagy has been implicated in pathogenesis of diverse diseases such as neurodegeneration and cancer. Due to the therapeutic potential, the autophagy-modulating agents have profoundly enriched the spectrum of tools used to investigate autophagy. However, many of these compounds have additional off-target effects that may confound elucidation of autophagy in certain contexts. There remains high demand for highly specific and novel chemotypes that can be used to study the regulation mechanism of autophagy and contribute novel pharmacophores for therapeutic purposes. Here, we describe a cell-based quantitative high-content screening (HCS) for autophagy inhibitors using a human breast adenocarcinoma MCF7 cell line stably expressing EGFP-LC3, a bona fide marker of autophagy.

Wang X, Jin Y, Li YX, Yang Y
Secretory leukocyte peptidase inhibitor expression and apoptosis effect in oral leukoplakia and oral squamous cell carcinoma.
Oncol Rep. 2018; 39(4):1793-1804 [PubMed] Related Publications
Oral leukoplakia (OL) is one of the most common oral precancerous lesions with the possibility of malignant transformation, ranging from 17 to 24% of patients with a median follow-up of >7 years. Previous research has revealed that compared with normal oral epithelial tissues, the expression of secretory leukocyte peptidase inhibitor (SLPI) protein is significantly reduced in oral squamous cell carcinoma (OSCC). Based on the above-mentioned research, it is known that SLPI is a potential predictive and diagnostic tool for the progression of oral carcinogenesis. Therefore, we investigated the correlation between the abundance of SLPI protein and the different histological grades of OL by immunohistochemistry. The results indicated that the level of SLPI was negatively correlated with the histological grades of the oral premalignant lesions, indicating that it may be a potential predictive tool for the malignant transformation presented in oral precancerous patients. Subsequently, we investigated the biological effects of SLPI using Cell Counting Kit (CCK)-8, Annexin V/PI apoptosis assay and Caspase-Glo® 3/7 assay. The findings revealed that SLPI promoted apoptosis in the Leuk1 and WSU-HN4 cell lines. Mechanistic studies indicated that SLPI, at least in part, regulated cell apoptosis by inhibiting the expression of TNF receptor-associated factor 1 (TRAF1), which has a close relationship with the nuclear factor-κB (NF-κB) pathway.

Lu JW, Yang F, Ke QF, et al.
Magnetic nanoparticles modified-porous scaffolds for bone regeneration and photothermal therapy against tumors.
Nanomedicine. 2018; 14(3):811-822 [PubMed] Related Publications
For effectively treating tumor related-bone defects, design and fabrication of multifunctional biomaterials still remain a great challenge. Herein, we firstly fabricated magnetic SrFe

Chang BY, Kim DS, Kim HS, Kim SY
Evaluation of estrogenic potential by herbal formula, HPC 03 for
Reproduction. 2018; 155(2):105-115 [PubMed] Related Publications
HPC 03 is herbal formula that consists of extracts from

Quabius ES, Merz I, Görögh T, et al.
miRNA-expression in tonsillar squamous cell carcinomas in relation to HPV infection and expression of the antileukoproteinase SLPI.
Papillomavirus Res. 2017; 4:26-34 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
The aim of this study was to determine if micro-(mi-)RNAs are involved in the previously reported inverse correlation between the antileukoproteinase SLPI, HPV, and smoking habit of head and neck squamous cells carcinoma (HNSCC) patients. HPV-status and SLPI-protein expression were determined in tonsillar SCC (TSCC; n=126). Differentially expressed miRNAs dependent on HPV-status and SLPI-expression were detected by microarray; possible binding-sites in SLPI- and HPVE6-mRNAs were determined in silico. Survival rates were estimated testing prognostic values of HPV-status, SLPI- and miRNA-expression. miRNA-array identified 24 up-regulated and 10 down-regulated miRNAs in HPV-positive versus HPV-negative TSCC (p<0.01; HPV-positivity: 42.1%). HPV-positivity resulted in two up-regulated miRNAs in SLPI-positive TSCC. Of 16 further miRNAs, eight miRNAs were up- and eight were down-regulated in SLPI-negative TSCC. RT-q-PCR-validation of the four most differentially expressed miRNAs showed that miR-363 is expressed strongest in SLPI-negative/HPV-positive TSSC. In silico-analysis of all differentially expressed miRNAs identified miR-363, miR-210, miR-130a, and miR-181a with possible binding sites in the HPV16-E6-mRNA, but none were predicted in the SLPI-mRNA. HPV-positivity, low SLPI-levels and high miR-363-levels are significantly associated with better survival rates. The data presented here show that miR-363 is associated with HPV-positive/SPLI-negative TSCC. The prognostic value of miR-363 suggests a role in the assumed inverse correlation of smoking and SPLI-expression in the mode of HPV-infections in tonsillar but possibly also other HNSCC.

Shi Y, Ye P, Long X
Differential Expression Profiles of the Transcriptome in Breast Cancer Cell Lines Revealed by Next Generation Sequencing.
Cell Physiol Biochem. 2017; 44(2):804-816 [PubMed] Related Publications
BACKGROUND/AIMS: As MCF-7 and MDA-MB-231 cells are the typical cell lines of two clinical breast tumour subtypes, the aim of the present study was to elucidate the transcriptome differences between MCF-7 and MDA-MB-231 breast cancer cell lines.
METHODS: The mRNA, miRNA (MicroRNA) and lncRNA (Long non-coding RNA) expression profiles were examined using NGS (next generation sequencing) instrument Illumina HiSeq-2500. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analyses were performed to identify the biological functions of differentially expressed coding RNAs. Subsequently, we constructed an mRNA-ncRNA (non-coding RNA) targeting regulatory network. Finally, we performed RT-qPCR (real-time quantitative PCR) to confirm the NGS results.
RESULTS: There are sharp distinctions of the coding and non-coding RNA profiles between MCF-7 and MDA-MB-231 cell lines. Among the mRNAs and ncRNAs with the most differential expression, SLPI, SOD2, miR-7, miR-143 and miR-145 were highly expressed in MCF-7 cells, while CD55, KRT17, miR-21, miR-10b, miR-9, NEAT1 and PICSAR were over-expressed in MDA-MB-231 cells. Differentially expressed mRNAs are primarily involved in biological processes of locomotion, biological adhesion, ECM-receptor interaction pathway and focal adhesion. In the targeting regulatory network of differentially expressed RNAs, mRNAs and miRNAs are primarily associated with tumour metastasis, but the functions of lncRNAs remain uncharacterized.
CONCLUSION: These results provide a basis for future studies of breast cancer metastasis and drug resistance.

Sakabe T, Azumi J, Umekita Y, et al.
Expression of Cancer Stem Cell-associated
Anticancer Res. 2017; 37(9):4881-4888 [PubMed] Related Publications
BACKGROUND/AIM: Cancer stem cells (CSCs) are associated with prognosis of hepatocellular carcinoma (HCC). In our previous study, we created cDNA microarray databases on the CSC population of human HuH7 cells. In the present study, we identified genes that might serve as prognostic markers of HCC by employing existing databases.
MATERIALS AND METHODS: Expressions of glutathione S-transferase pi 1 (GSTP1), lysozyme (LYZ), C-X-C motif chemokine ligand 5 (CXCL5), interleukin-8 (IL8) and dickkopf WNT signaling pathway inhibitor 1 (DKK1), the five most highly expressed genes in the CSC cDNA microarray databases, were examined in 99 patients with HCC by real-time polymerase chain reaction (qRT-PCR), and their clinical significance was analyzed.
RESULTS: The Kaplan-Meier analysis showed that both overall and cancer-specific survival were significantly longer in patients with low DKK1 expression than in those with high DKK1 expression. The multivariate analysis revealed that overall survival was negatively associated with albumin and positively associated with alkaline phosphatase (ALP), serosal invasion and stage, and cancer-specific survival was positively associated with ALP, portal vein invasion and DKK1 mRNA.
CONCLUSION: Expression of CSC-associated DKK1 mRNA might be an unfavorable prognostic marker for patients with HCC.

Hida K, Maishi N, Akiyama K, et al.
Tumor endothelial cells with high aldehyde dehydrogenase activity show drug resistance.
Cancer Sci. 2017; 108(11):2195-2203 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
Tumor blood vessels play an important role in tumor progression and metastasis. We previously reported that tumor endothelial cells (TEC) exhibit several altered phenotypes compared with normal endothelial cells (NEC). For example, TEC have chromosomal abnormalities and are resistant to several anticancer drugs. Furthermore, TEC contain stem cell-like populations with high aldehyde dehydrogenase (ALDH) activity (ALDH

Kwon YC, Sasaki R, Meyer K, Ray R
Hepatitis C Virus Core Protein Modulates Endoglin (CD105) Signaling Pathway for Liver Pathogenesis.
J Virol. 2017; 91(21) [PubMed] Article available free on PMC after 01/09/2019 Related Publications
Endoglin is part of the TGF-β receptor complex and has a crucial role in fibrogenesis and angiogenesis. It is also an important protein for tumor growth, survival, and cancer cell metastasis. In a previous study, we have shown that hepatitis C virus (HCV) infection induces epithelial-mesenchymal transition (EMT) state and cancer stem-like cell (CSC) properties in human hepatocytes. Our array data suggested that endoglin (CD105) mRNA is significantly upregulated in HCV-associated CSCs. In this study, we have observed increased endoglin expression on the cell surface of an HCV core-expressing hepatocellular carcinoma (HepG2) cell line or immortalized human hepatocytes (IHH) and activation of its downstream signaling molecules. The status of phospho-SMAD1/5 and the expression of inhibitor of DNA binding protein 1 (ID1) were upregulated in HCV-infected cells or viral core gene-transfected cells. Additionally, we observed upregulation of endoglin/ID1 mRNA expression in chronic HCV patient liver biopsy samples. CSC generation by HCV core protein was dependent on the endoglin signaling pathway using activin receptor-like kinase 1 (ALK1) Fc blocking peptide and endoglin small interfering RNA (siRNA). Further, follow-up from

Kim J, Lee HW, Rhee DK, et al.
Pneumolysin-induced autophagy contributes to inhibition of osteoblast differentiation through downregulation of Sp1 in human osteosarcoma cells.
Biochim Biophys Acta Gen Subj. 2017; 1861(11 Pt A):2663-2673 [PubMed] Related Publications
BACKGROUND INFORMATION: The 53kDa protein pneumolysin (PLY) is the main virulence factor of Streptococcus pneumoniae, a leading cause of invasive pneumococcal diseases. PLY forms pores in cholesterol-containing membranes, thereby interfering with the function of cells. Bone destruction is a serious matter in chronic inflammatory diseases such as septic arthritis and osteomyelitis. S. pneumoniae is increasingly being recognized as a common cause of septic arthritis, but its pathogenesis is poorly defined.
METHOD: We examined the effect of PLY on osteoblast differentiation and its mechanisms of action. The effect of PLY on osteoblast differentiation was evaluated by qRT-PCR, ALP activity assay, flow cytometric analysis, and Western blotting. We also examined the role of PLY-induced autophagy in osteoblast differentiation using RNA interference analysis.
RESULTS: PLY inhibited osteoblast differentiation by decreasing the expression of osteoblast marker genes such as Runx2 and OCN, along with ALP activity. ROS production was increased by PLY during osteoblast differentiation. PLY induced autophagy through ROS-mediated regulation of AMPK and mTOR, which downregulated the expression of Sp1 and subsequent inhibition of differentiation. Treatment with autophagy inhibitors or Atg5 siRNA alleviated the PLY-induced inhibition of differentiation.
CONCLUSION: The results suggest that PLY inhibits osteoblast differentiation by downregulation of Sp1 accompanied by induction of autophagy through ROS-mediated regulation of the AMPK/mTOR pathway.
GENERAL SIGNIFICANCE: This study proposes a molecular mechanism for inhibition of osteoblast differentiation in response to PLY.

Ye R, Pi M, Cox JV, et al.
CRISPR/Cas9 targeting of GPRC6A suppresses prostate cancer tumorigenesis in a human xenograft model.
J Exp Clin Cancer Res. 2017; 36(1):90 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
BACKGROUND: GPRC6A is implicated in the pathogenesis of prostate cancer, but its role remains uncertain because of a purported tolerant gene variant created by substitution of a K..Y polymorphism in the 3rd intracellular loop (IL) that evolved in the majority of humans and replaces the ancestral RKLP present in 40% of humans of African descent and all other species.
METHODS: We determined whether the K..Y polymorphism is present in human-derived prostate cancer cell lines by sequencing the region of the 3rd IL and assessed the cellular localization of a "humanized" mouse GPRC6A containing the K..Y sequence by immunofluorescence. We assessed functions of GPRC6A in PC-3 cells expressing endogenous GPRC6A and in GPRC6A-deficient PC-3 cells created using CRISPR/Cas9 technology. The effect of GPRC6A on basal and ligand stimulated cell proliferation and migration was evaluated in vitro in wild-type and PC-3-deficient cell lines. The effect of editing GPRC6A on prostate cancer growth and progression in vivo was assessed in a Xenograft mouse model implanted with wild-type and PC-3 deficient cells and treated with the GPRC6A ligand osteocalcin.
RESULTS: We found that all of the human prostate cancer cell lines tested endogenously express the "K..Y" polymorphism in the 3rd IL. Comparison of mouse wild-type GPRC6A with a "humanized" mouse GPRC6A construct created by replacing the "RKLP" with the "K..Y" sequence, found that both receptors were predominantly expressed on the cell surface. The transfected "humanized" GPRC6A receptor, however, preferentially activated mTOR compared to ERK signaling in HEK-293 cells. In contrast, in PC-3 cells expressing the endogenous GPRC6A with the "K..Y" polymorphism, the ligand osteocalcin stimulated ERK, AKT and mTOR phosphorylation, promoted cell proliferation and migration, and upregulated genes regulating testosterone biosynthesis. Targeting GPRC6A in PC-3 cells by CRISPR/Cas9 significantly blocked these responses in vitro. In addition, GPRC6A deficient PC-3 xenografts exhibited significantly less growth and were resistant to osteocalcin-induced prostate cancer progression compared to control PC-3 cells expressing GPRC6A.
CONCLUSIONS: Human GPRC6A is a functional osteocalcin and testosterone sensing receptor that promotes prostate cancer progression. GPRC6A may contribute to racial disparities in prostate cancer, and is a potential therapeutic target to develop antagonists to treat prostate cancer.

Takamura T, Suguro H, Mikami Y, et al.
Comparison of gene expression profiles of gingival carcinoma Ca9-22 cells and colorectal adenocarcinoma HT-29 cells to identify potentially important mediators of SLPI-induced cell migration.
J Oral Sci. 2017; 59(2):279-287 [PubMed] Related Publications
Secretory leukocyte protease inhibitor (SLPI) is a serine protease inhibitor whose expression level is positively correlated with tumor aggressiveness and metastatic potential. However, the mechanism underlying SLPI-induced enhancement of malignant phenotype is not completely understood. The malignancy of cancer cells is highly dependent on cell migration activity. Our previous study revealed that gingival carcinoma Ca9-22 cells, but not colorectal adenocarcinoma HT-29 cells, expressed SLPI. Therefore, we investigated the migration activity of these two cell types to understand the nature of SLPI-mediated tumor aggressiveness and metastatic potential. In vitro wound healing assay indicated that HT-29 cells and SLPI-deleted Ca9-22 cells showed lower migration activity than wild-type Ca9-22 cells, suggesting that SLPI-induced cell migration plays an important role in tumor aggressiveness and metastatic potential. In addition, our gene expression profiling study based on microarray data for the three cell types identified a number of candidates, including LCP1 and GLI, that could be key molecules in the mechanism of SLPI-induced cell migration.

Ratz L, Laible M, Kacprzyk LA, et al.
TMPRSS2:ERG gene fusion variants induce TGF-β signaling and epithelial to mesenchymal transition in human prostate cancer cells.
Oncotarget. 2017; 8(15):25115-25130 [PubMed] Article available free on PMC after 01/09/2019 Related Publications
TMPRSS2:ERG (T/E) gene fusions are present in approximately 50% of all prostate cancer (PCa) cases. The expression of fusion mRNAs from distinct T/E variants is associated with clinicopathological parameters, while the underlying molecular processes remain unclear. We characterized the molecular mechanisms and functional implications caused by doxycycline (Dox)-inducible overexpression of the frequent T/E III and VI fusion variants in LNCaP cells. Induction of T/E expression resulted in increased cellular migratory and invasive potential, and reduced proliferation and accumulation in G1 phase. T/E overexpressing cells showed epithelial-to-mesenchymal transition (EMT), as demonstrated by upregulation of TGF-β and WNT pathway genes, mesenchymal markers, and increased phosphorylation of the p38 MAPK. Augmented secretion of TGF-β1 and -β2, and T/E-mediated regulation of ALK1, a member of the TGF-β receptor family, was detected. ALK1 inhibition in T/E overexpressing cells blocked p38 phosphorylation and reduced the expression of the TGF-β target genes VIM, MMP1, CDH2, and SNAI2. We found a T/E variant VI-specific induction of miR-503 associated with reduced expression of SMAD7 and CDH1. Overexpression of miR-503 led to increased levels of VIM and MMP1. Our findings indicate that TGF-β signaling is a major determinant of EMT in T/E overexpressing LNCaP cells. We provide evidence that T/E VI-specific transcriptional modulation by miR-503 accounts for differences in the activation of EMT pathway genes, promoting the aggressive phenotype of tumors expressing T/E variant VI. We suggest that ALK1-mediated TGF-β signaling is a novel oncogenic mechanism in T/E positive PCa.

Shi J, Hou S, Huang J, et al.
An MSN-PEG-IP drug delivery system and IL13Rα2 as targeted therapy for glioma.
Nanoscale. 2017; 9(26):8970-8981 [PubMed] Related Publications
A combination of gene therapy and chemotherapy has recently received interest as a targeted therapy for glioma. A mesoporous silica nanoparticle (MSN)-based vehicle coated with IL13Rα2-targeted peptide (IP) using polyethylene glycol (PEG), MSN-PEG-IP (MPI), was constructed and confirmed as a potential glioma-targeted drug delivery system in vitro. In this work, tissue microarray (TMA) results revealed that IL13Rα2 was over-expressed in human glioma tissues and that high expression of IL13Rα2 in patients was associated with poor survival. Doxorubicin (DOX)-loaded MPI (MPI/D) crossed the blood-brain barrier, specifically targeting glioma cells and significantly enhancing the cellular uptake of DOX in glioma cells compared with MSN/DOX (M/D) and MSN-PEG/DOX (MP/D), whereas the normal brain was not affected. Magnetic Resonance Imaging (MRI) examinations showed that the tumour size of glioma-bearing rats in the MPI/D-treated group was much smaller than those in the M/D and MP/D treated groups. Immunofluorescence results demonstrated that MPI/D treatment induced more apoptosis and much less proliferation than the other two treatments. However, the therapeutic effect was weak when IL13Rα2 was knocked down. Furthermore, U87 cells treated with IL-13 and MPI together could increase both STAT6 and P63 expression, which attenuated glioma cell proliferation, invasion and migration compared with cells treated with IL-13 alone. The results of the subcutaneous tumour model also revealed that IL13Rα2 knockdown could hinder cell proliferation and induce more apoptosis. The promising results suggested that MPI can not only deliver DOX to glioma in a targeted manner but also occupy IL13Rα2, which can promote IL-13 binding to IL13Rα1 and activation of the JAK-STAT pathway to induce an anti-glioma effect.

Du XY, Liu X, Wang ZJ, Wang YY
SLPI promotes the gastric cancer growth and metastasis by regulating the expression of P53, Bcl-2 and Caspase-8.
Eur Rev Med Pharmacol Sci. 2017; 21(7):1495-1501 [PubMed] Related Publications
OBJECTIVE: The incidence of gastric cancer is very high all over the world, but the mechanism of the occurrence and development of gastric cancer is unclear. Secretory leukocyte protease inhibitor (SLPI) is overexpressed in gastric, lung and ovarian cancers, which accelerates the metastasis of cancer cells. In this research, we mainly explored the expression level and possible mechanism of SLPI in gastric cancer.
PATIENTS AND METHODS: The expression and clinical significance of SLPI in 68 cases of gastric cancer tissues and adjacent tissues were detected by qRT-PCR. Cell Counting Kit-8 (CCK8) assay was used to detect the proliferation ability of gastric cancer cell lines. In addition, we used Western blot to clarify the relationship between SLPI and metastasis.
RESULTS: Compared with the adjacent tissues, we found that SLPI was highly expressed in gastric cancer tissues. We also found that the expression of SLPI was in significant correlation with the survival time, clinical classification and size of the tumor. What's more, SLPI could promote the proliferation and metastasis of gastric cancer by regulating P53, Bcl-2 and Caspase-8 expression through apoptosis signaling pathway.
CONCLUSIONS: We concluded that SLPI was closely related with to invasion and metastasis of gastric cancer. Perhaps we can hopefully find new targets for the treatment of gastric cancer.

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