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, VEGA, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 20 August, 2015


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 (1990-2015)
Graph generated 20 August 2015 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.

  • Up-Regulation
  • Western Blotting
  • Proteins
  • Tissue Array Analysis
  • Proteinase Inhibitory Proteins, Secretory
  • Carcinoma
  • Signal Transduction
  • Microarray Analysis
  • Ovarian Cancer
  • Gene Expression Profiling
  • Secretory Leukocyte Peptidase Inhibitor
  • Oligonucleotide Array Sequence Analysis
  • Cell Division
  • Stomach Cancer
  • Transcriptional Activation
  • Cell Growth Processes
  • Squamous Cell Carcinoma
  • Neoplasm Proteins
  • Adenoviridae
  • Seminal Vesicles
  • Cystadenocarcinoma, Serous
  • Uterine Cancer
  • Messenger RNA
  • Lung Cancer
  • Chromosome 20
  • Tumor Markers
  • Cervical Cancer
  • Young Adult
  • Genetic Therapy
  • beta-Defensins
  • Immunohistochemistry
  • Base Sequence
  • Cytomegalovirus
  • Breast Cancer
  • Gene Expression
  • Tissue Kallikreins
  • Promoter Regions
  • Cell Movement
  • Cancer Gene Expression Regulation
Tag cloud generated 20 August, 2015 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: SLPI (cancer-related)

Chen Z, Shojaee S, Buchner M, et al.
Signalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia.
Nature. 2015; 521(7552):357-61 [PubMed] Article available free on PMC after 21/11/2015 Related Publications
B cells are selected for an intermediate level of B-cell antigen receptor (BCR) signalling strength: attenuation below minimum (for example, non-functional BCR) or hyperactivation above maximum (for example, self-reactive BCR) thresholds of signalling strength causes negative selection. In ∼25% of cases, acute lymphoblastic leukaemia (ALL) cells carry the oncogenic BCR-ABL1 tyrosine kinase (Philadelphia chromosome positive), which mimics constitutively active pre-BCR signalling. Current therapeutic approaches are largely focused on the development of more potent tyrosine kinase inhibitors to suppress oncogenic signalling below a minimum threshold for survival. We tested the hypothesis that targeted hyperactivation--above a maximum threshold--will engage a deletional checkpoint for removal of self-reactive B cells and selectively kill ALL cells. Here we find, by testing various components of proximal pre-BCR signalling in mouse BCR-ABL1 cells, that an incremental increase of Syk tyrosine kinase activity was required and sufficient to induce cell death. Hyperactive Syk was functionally equivalent to acute activation of a self-reactive BCR on ALL cells. Despite oncogenic transformation, this basic mechanism of negative selection was still functional in ALL cells. Unlike normal pre-B cells, patient-derived ALL cells express the inhibitory receptors PECAM1, CD300A and LAIR1 at high levels. Genetic studies revealed that Pecam1, Cd300a and Lair1 are critical to calibrate oncogenic signalling strength through recruitment of the inhibitory phosphatases Ptpn6 (ref. 7) and Inpp5d (ref. 8). Using a novel small-molecule inhibitor of INPP5D (also known as SHIP1), we demonstrated that pharmacological hyperactivation of SYK and engagement of negative B-cell selection represents a promising new strategy to overcome drug resistance in human ALL.

Aoude LG, Pritchard AL, Robles-Espinoza CD, et al.
Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma.
J Natl Cancer Inst. 2015; 107(2) [PubMed] Article available free on PMC after 01/02/2016 Related Publications
BACKGROUND: The shelterin complex protects chromosomal ends by regulating how the telomerase complex interacts with telomeres. Following the recent finding in familial melanoma of inactivating germline mutations in POT1, encoding a member of the shelterin complex, we searched for mutations in the other five components of the shelterin complex in melanoma families.
METHODS: Next-generation sequencing techniques were used to screen 510 melanoma families (with unknown genetic etiology) and control cohorts for mutations in shelterin complex encoding genes: ACD, TERF2IP, TERF1, TERF2, and TINF 2. Maximum likelihood and LOD [logarithm (base 10) of odds] analyses were used. Mutation clustering was assessed with χ(2) and Fisher's exact tests. P values under .05 were considered statistically significant (one-tailed with Yates' correction).
RESULTS: Six families had mutations in ACD and four families carried TERF2IP variants, which included nonsense mutations in both genes (p.Q320X and p.R364X, respectively) and point mutations that cosegregated with melanoma. Of five distinct mutations in ACD, four clustered in the POT1 binding domain, including p.Q320X. This clustering of novel mutations in the POT1 binding domain of ACD was statistically higher (P = .005) in melanoma probands compared with population control individuals (n = 6785), as were all novel and rare variants in both ACD (P = .040) and TERF2IP (P = .022). Families carrying ACD and TERF2IP mutations were also enriched with other cancer types, suggesting that these variants also predispose to a broader spectrum of cancers than just melanoma. Novel mutations were also observed in TERF1, TERF2, and TINF2, but these were not convincingly associated with melanoma.
CONCLUSIONS: Our findings add to the growing support for telomere dysregulation as a key process associated with melanoma susceptibility.

Quabius ES, Görögh T, Fischer GS, et al.
The antileukoprotease secretory leukocyte protease inhibitor (SLPI) and its role in the prevention of HPV-infections in head and neck squamous cell carcinoma.
Cancer Lett. 2015; 357(1):339-45 [PubMed] Related Publications
Recently, we demonstrated a significant inverse correlation between HPV-infection and SLPI-expression suggesting that SLPI protects against HPV-infection of HNSCC. Here we analyzed in a single lab setting 307 formalin-fixed paraffin-embedded HNSCC cases (tonsillar n = 135; non-tonsillar: n = 172) from eight health care centers. Samples were analyzed for SLPI gene- and protein-expression. Annexin A2, its heterotetramer A2t, putatively facilitating HPV- and SLPI-cell entry, was measured to study the correlation between SLPI and annexin A2. Data were correlated with tobacco consumption and HPV-status. Overall, HPV-DNA prevalence was 23.5% (72/307); attributed to: 43.7% (59/135) tonsillar and 7.6% (13/172) non-tonsillar cases. Smoking resulted in 6.44-fold increased and HPV-infection in 3.46-fold decreased SLPI-gene expression in all HNSCC with similar significant results obtained in tonsillar and non-tonsillar SCC separately. Correlating annexin A2- and SLPI-gene expression showed a significant surplus of annexin A2 in HPV-positive tumors (4.21× more annexin A2) and 6.72× more annexin A2 than SLPI in nonsmokers in all HNSCCs and similar significant results for both tumor entities separately. The surplus of annexin A2 in non-smokers and HPV-positive patients supports our hypothesis that decreased SLPI levels facilitate HPV-infection i.e., increased SLPI-expression may protect against HPV-infection of tonsillar and non-tonsillar SCC.

Didiasova M, Wujak L, Wygrecka M, Zakrzewicz D
From plasminogen to plasmin: role of plasminogen receptors in human cancer.
Int J Mol Sci. 2014; 15(11):21229-52 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Cell surface-associated proteolysis mediated by plasmin (PLA) is an essential feature of wound healing, angiogenesis and cell invasion, processes that are dysregulated in cancer development, progression and systemic spread. The generation of PLA, initiated by the binding of its precursor plasminogen (PLG) to the cell surface, is regulated by an array of activators, inhibitors and receptors. In this review, we will highlight the importance of the best-characterized components of the PLG/PLA cascade in the pathogenesis of cancer focusing on the role of the cell surface-PLG receptors (PLG-R). PLG-R overexpression has been associated with poor prognosis of cancer patients and resistance to chemotherapy. We will also discuss recent findings on the molecular mechanisms regulating cell surface expression and distribution of PLG-R.

Sharma U, Pal D, Prasad R
A novel role of alkaline phosphatase in the ERK1/2 dephosphorylation in renal cell carcinoma cell lines: a new plausible therapeutic target.
Biochimie. 2014; 107 Pt B:406-9 [PubMed] Related Publications
Extracellular regulated kinase 1/2 (ERK1/2) has been shown to be activated in renal cell carcinoma (RCC). Previously, we have reported aberrant expression/activity of Liver/Bone/Kidney alkaline phosphatase (L/B/K ALP) in RCC. The present study was conducted to find out whether L/B/K ALP has any role in the dephosphorylation of ERK1/2 in renal cancer cell lines. Two renal cancer cell lines viz. ACHN and A498 were transfected with full length L/B/K ALP cDNA. ALP expression/activity and ERK1/2 phosphorylation were evaluated. Increased L/B/K ALP expression/activity was associated with significantly reduced (P = 0.001) phosphorylation status of ERK1/2 in ALP cDNA transfected cells in comparison to that of control. This is the first study that suggests deactivation of ERK1/2 by stimulation of ALP in renal cancer cell lines which can be used as a therapeutic target of RCC.

Chen B, Zhao AG, Shao J, et al.
The effects of PTBP3 silencing on the proliferation and differentiation of MKN45 human gastric cancer cells.
Life Sci. 2014; 114(1):29-35 [PubMed] Related Publications
AIMS: PTBP3 overexpression inhibits the differentiation of leukemia cells; however, its effects on the differentiation and proliferation of solid cancer cells remain unclear. Thus, the impact of PTBP3 on the differentiation and proliferation of gastric cancer cells was investigated.
MAIN METHODS: PTBP3 expression was analyzed in normal and tumor tissues using immunohistochemistry. A xenograft model was established in nude mice by subcutaneous injection of untransfected human gastric cancer MKN45 cells or those expressing a control vector or PTBP3 siRNA. We analyzed the tumor inhibition rate, the expression of PTBP3, the PCNA-positive rate and the serum levels of CEA, CA199, CA125, LDH, ALP and γ-GT in different groups.
KEY FINDINGS: The tumor weights in the PTBP3 siRNA group were significantly lower than that of the MKN45 cell control group (P<0.001). Immunohistochemistry analysis of PCNA expression revealed that it was markedly reduced after PTBP3 silencing. ELISAs showed that the serum levels of CEA and CA199 tumor markers as well as LDH and ALP were reduced after PTBP3 silencing. Transmission electron microscopy revealed that MKN45 cells expressing PTBP3 siRNA had reduced nuclear-to-cytoplasmic ratio and regular nuclei, suggesting differentiation.
SIGNIFICANCE: PTBP3 may promote proliferation and inhibit the differentiation of human gastric cancer MKN45 cells.

Shin J, Carr A, Corner GA, et al.
The intestinal epithelial cell differentiation marker intestinal alkaline phosphatase (ALPi) is selectively induced by histone deacetylase inhibitors (HDACi) in colon cancer cells in a Kruppel-like factor 5 (KLF5)-dependent manner.
J Biol Chem. 2014; 289(36):25306-16 [PubMed] Article available free on PMC after 05/09/2015 Related Publications
The histone deacetylase inhibitor (HDACi) sodium butyrate promotes differentiation of colon cancer cells as evidenced by induced expression and enzyme activity of the differentiation marker intestinal alkaline phosphatase (ALPi). Screening of a panel of 33 colon cancer cell lines identified cell lines sensitive (42%) and resistant (58%) to butyrate induction of ALP activity. This differential sensitivity was similarly evident following treatment with the structurally distinct HDACi, MS-275. Resistant cell lines were significantly enriched for those harboring the CpG island methylator phenotype (p = 0.036, Chi square test), and resistant cell lines harbored methylation of the ALPi promoter, particularly of a CpG site within a critical KLF/Sp regulatory element required for butyrate induction of ALPi promoter activity. However, butyrate induction of an exogenous ALPi promoter-reporter paralleled up-regulation of endogenous ALPi expression across the cell lines, suggesting the presence or absence of a key transcriptional regulator is the major determinant of ALPi induction. Through microarray profiling of sensitive and resistant cell lines, we identified KLF5 to be both basally more highly expressed as well as preferentially induced by butyrate in sensitive cell lines. KLF5 overexpression induced ALPi promoter-reporter activity in resistant cell lines, KLF5 knockdown attenuated butyrate induction of ALPi expression in sensitive lines, and butyrate selectively enhanced KLF5 binding to the ALPi promoter in sensitive cells. These findings demonstrate that butyrate induction of the cell differentiation marker ALPi is mediated through KLF5 and identifies subsets of colon cancer cell lines responsive and refractory to this effect.

Zhu XS, Lin ZY, Du J, et al.
BCR/ABL mRNA targeting small interfering RNA effects on proliferation and apoptosis in chronic myeloid leukemia.
Asian Pac J Cancer Prev. 2014; 15(12):4773-80 [PubMed] Related Publications
BACKGROUND: To investigate the effects of small interference RNA (siRNA) targeting BCR/ABL mRNA on proliferation and apoptosis in the K562 human chronic myeloid leukemia (CML) cell line and to provide a theoretical rationale and experimental evidence for its potential clinical application for anti-CML treatment.
MATERIALS AND METHODS: The gene sequence for BCR/ABL mRNA was found from the GeneBank. The target gene site on the BCR/ABL mRNA were selected according to Max-Planck-Institute (MPI) and rational siRNA design rules, the secondary structure of the candidate targeted mRNA was predicted, the relevant thermodynamic parameters were analyzed, and the targeted gene sequences were compared with BLAST to eliminate any sequences with significant homology. Inhibition of proliferation was evaluated by MTT assay and colony-formation inhibiting test. Apoptosis was determined by flow cytometry (FCM) and the morphology of apoptotic cells was identified by Giemsa-Wright staining. Western blotting was used to analyze the expression of BCR/ABL fusion protein in K562 cells after siRNA treatment.
RESULTS: The mRNA local secondary structure calculated by RNA structure software, and the optimal design of specific siRNA were contributed by bioinformatics rules. Five sequences of BCR/ABL siRNAs were designed and synthesized in vitro. Three sequences, siRNA1384, siRNA1276 and siRNA1786, which showed the most effective inhibition of K562 cell growth, were identified among the five candidate siRNAs, with a cell proliferative inhibitory rate nearly 50% after exposure to 12.5 nmol/L~50 nmol/L siRNA1384 for 24,48 and 72 hours. The 50% inhibitory concentrations (IC50) of siRNA1384, siRNA1276 and siRNA1786 for 24 hours were 46.6 nmol/L, 59.3 nmol/L and 62.6 nmol/L, respectively, and 65.668 nmol/L, 76.6 nmol/L, 74.4 nmol/L for 72 hours. The colony-formation inhibiting test also indicated that, compared with control, cell growth of siRNA treated group was inhibited. FCM results showed that the rate of cell apoptosis increased 24 hours after transfecting siRNA. The results of annexinV/PI staining indicated that the rate of apoptosis imcreased (1.53%, 15.3%, 64.5%, 57.5% and 21.5%) following treamtne with siRNAs (siRNA34, siRNA372, siRNA1384, siRNA1276 and siRNA1786). Morphological analysis showed td typical morphologic changes of apoptosis such as shrunken, fragmentation nucleus as well as "apoptotic bodies" after K562 cell exposure to siRNA. Western blot analysis showed that BCR/ABL protein was reduced sharply after a single dose of 50 nmol/L siRNA transfection.
CONCLUSIONS: Proliferation of K562 cells was remarkbly inhibited by siRNAs (siRNA1384, siRNA1276 and siRNA1786) in a concentration-dependent manner in vitro, with effective induction of apoptosis at a concentration of 50 nmol/L. One anti-leukemia mechanism in K562 cells appeared that BCR/ABL targeted protein was highly down-regulated. The siRNAs (siRNA1384, siRNA1276 and siRNA1786) may prove valuable in the treatment of CML.

Martinotti S, Mazzucco L, Balbo V, et al.
Platelet-rich plasma induces mixed osteogenic/osteoclastogenic phenotype in osteosarcoma SaOS-2 cells: role of TGF-beta.
Curr Pharm Biotechnol. 2014; 15(2):120-6 [PubMed] Related Publications
Platelet-rich plasma (PRP) is widely used to promote tissue repair and accelerate osteogenesis, but there is no agreement about its mechanism of action. We characterized the modulatory effect of PRP on the in vitro osteoblast model SaOS-2, by using cell motility/chemoattraction and osteogenesis/mineralization assays, and a series of osteogenic/ osteoclastogenic genomic markers. Scratch wound assay showed that PRP stimulates cell motility, while transwell assay revealed a strong chemoattraction. Alkaline phosphatase (ALP) and alizarin red-S assays showed that PRP induces slight, but significant, stimulations of ALP activity and mineralization. The TGF-β inhibitor SB431542 reversed these effects, showing a main role for TGF-β1 released by PRP. Analyses of gene expression by qRT-PCR, showed the upregulation of osteocalcin, osteopontin, osteoprotegerin, receptor activator of NFκB (RANK), and runt-related transcription factor 2 (RUNX2) genes, with a total reversion by SB431542 for osteoprotegerin and RANK, and a partial reversion for ostecalcin, osteopontin, and RUNX2. The use of PCR array technique revealed the upregulation of the cathepsin K gene. These data show that PRP induces the development of mixed osteogenic/osteoclastogenic traits in the SaOS-2 model. Such a behavior may favour in vivo bone resorption and reconstitution at post-surgery or post-traumatic sites.

Sharma U, Pal D, Singh SK, et al.
Reduced L/B/K alkaline phosphatase gene expression in renal cell carcinoma: plausible role in tumorigenesis.
Biochimie. 2014; 104:27-35 [PubMed] Related Publications
Renal cell carcinoma (RCC) is the most common kidney cancer in adults. Although several genes have been found to be involved in carcinogenesis of RCC, more great efforts are needed to identify new genes which are responsible for the process. Clear cell RCC, originates from proximal tubule cells, is the most common pathological type of RCC. Alkaline phosphatase (ALP) is a marker enzyme of brush border membrane of proximal tubular cells. Our previous studies showed a significant decreased activity of Liver/Bone/Kidney (L/B/K) alkaline phosphatase in RCC. In the present study, we explored the molecular basis of the decreased activity of ALP in RCC. Immunohistochemistry, immunofluorescence and flow cytometry analysis showed decreased ALP protein in RCC. Additionally, real time PCR documented significantly reduced ALP gene expression (P = 0.009). Moreover, RCC cell lines (ACHN and A498) transfected with full length L/B/K cDNA showed decreased migratory property as well as viability of these cells as compared with controls (P = 0.000). Further, L/B/K ALP cDNA transfected cells (ACHN and A498) showed significant increased apoptosis as compared to control (P = 0.000). These findings suggest the new role of ALP in cell viability and apoptosis and involvement in RCC tumorigenesis. However, further studies are needed to explore the exact molecular mechanism.

Demidova I, Barinov A, Savelov N, et al.
Immunohistochemistry, fluorescence in situ hybridization, and reverse transcription-polymerase chain reaction for the detection of anaplastic lymphoma kinase gene rearrangements in patients with non-small cell lung cancer: potential advantages and methodologic pitfalls.
Arch Pathol Lab Med. 2014; 138(6):794-802 [PubMed] Related Publications
CONTEXT: Echinoderm microtubule-associated protein-like 4 gene (EML4) and anaplastic lymphoma kinase gene (ALK) fusion was shown to be the driver of tumorigenesis in approximately 3% to 5% of patients with non-small cell lung cancer (NSCLC) and is associated with response to inhibition with crizotinib. However, no complete agreement regarding the best diagnostic test for identification of ALK rearrangements has been achieved yet.
OBJECTIVE: To investigate the concordance, sensitivity, and specificity of immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and reverse transcription-polymerase chain reaction (RT-PCR) for detection of ALK rearrangements.
DESIGN: Thirty-six prospectively tested patients with NSCLC who had adenocarcinoma and 10 ALK-positive samples were included in the study. All samples were tested by IHC (ALK1 clone, 5A4 clone, D5F3 clone), FISH (LSI ALK Break Apart and ALK FISH Probe), and multiplexed RT-PCR.
RESULTS: Immunohistochemistry staining was successful in all samples.. Clone D5F3 showed the best sensitivity and specificity of 100%; clones ALK1 and 5A4 showed sensitivities of 91% with specificity of 100%. Both FISH probes showed concordance with sensitivity and specificity of 100%. Hybridization and RT-PCR were successful in 98% and 93.4% of samples, respectively, with sensitivity of 88% and specificity of 100%. Frequent artifacts leading to misinterpretation were observed with all 3 methodologies.
CONCLUSIONS: All 3 methodologies showed good sensitivity, specificity, and concordance, when artifacts were characterized and excluded. However, all ambiguous cases have to be confirmed as ALK rearranged by at least 2 of the 3 methods.

Le Quesne J, Maurya M, Yancheva SG, et al.
A comparison of immunohistochemical assays and FISH in detecting the ALK translocation in diagnostic histological and cytological lung tumor material.
J Thorac Oncol. 2014; 9(6):769-74 [PubMed] Article available free on PMC after 05/09/2015 Related Publications
INTRODUCTION: Detection of the ALK rearrangement in a solid tumor gives these patients the option of crizotinib as an oral form of anticancer treatment. The current test of choice is fluorescence in situ hybridization (FISH), but various cheaper and more convenient immunohistochemical (IHC) assays have been proposed as alternatives.
METHODS: Fifteen FISH-positive cases from patients, seven with data on crizotinib therapy and clinical response, were evaluated for the presence of ALK protein using three different commercially available antibodies: D5F3, using the proprietary automated system (Ventana), ALK1 (Dako), and 5A4 (Abcam). A further 14 FISH-negative and three uncertain (<15% rearrangement detected) cases were also retrieved. Of the total 32 specimens, 17 were excisions and 15 were computed tomography-guided biopsies or cytological specimens. All three antibodies were applied to all cases. Antibodies were semiquantitatively scored on intensity, and the proportion of malignant cells stained was documented. Cutoffs were set by receiver operating curve analysis for positivity to optimize correct classification.
RESULTS: All three IHC assays were 100% specific but sensitivity did vary: D5F3 86%, ALK 79%, 5A4 71%. Intensity was the most discriminating measure overall, with a combination of proportion and intensity not improving the test. No FISH-negative IHC-positive cases were seen. Two FISH-positive cases were negative with all three IHC assays. One of these had been treated with crizotinib and had failed to show clinical response. The other harbored a second driving mutation in the EGFR gene.
CONCLUSIONS: IHC with all three antibodies is especially highly specific (100%) although variably sensitive (71%-86%), specifically in cases with scanty material. D5F3 assay was most sensitive in these latter cases. Occasional cases are IHC-positive but FISH-negative, suggesting either inaccuracy of one assay or occasional tumors with ALK rearrangement that do not express high levels of ALK protein.

Yang Y, Rhodus NL, Ondrey FG, et al.
Quantitative proteomic analysis of oral brush biopsies identifies secretory leukocyte protease inhibitor as a promising, mechanism-based oral cancer biomarker.
PLoS One. 2014; 9(4):e95389 [PubMed] Article available free on PMC after 05/09/2015 Related Publications
A decrease in the almost fifty percent mortality rate from oral cancer is needed urgently. Improvements in early diagnosis and more effective preventive treatments could affect such a decrease. Towards this end, we undertook for the first time an in-depth mass spectrometry-based quantitative shotgun proteomics study of non-invasively collected oral brush biopsies. Proteins isolated from brush biopsies from healthy normal tissue, oral premalignant lesion tissue (OPMLs), oral squamous cell carcinoma (OSCC) and matched control tissue were compared. In replicated proteomic datasets, the secretory leukocyte protease inhibitor (SLPI) protein stood out based on its decrease in abundance in both OPML and OSCC lesion tissues compared to healthy normal tissue. Western blotting in additional brushed biopsy samples confirmed a trend of gradual decreasing SLPI abundance between healthy normal and OPML tissue, with a larger decrease in OSCC lesion tissue. A similar SLPI decrease was observed in-vitro comparing model OPML and OSCC cell lines. In addition, exfoliated oral cells in patients' whole saliva showed a loss of SLPI correlated with oral cancer progression. These results, combined with proteomics data indicating a decrease in SLPI in matched healthy control tissue from OSCC patients compared to tissue from healthy normal tissue, suggested a systemic decrease of SLPI in oral cells correlated with oral cancer development. Finally, in-vitro experiments showed that treatment with SLPI significantly decreased NF-kB activity in an OPML cell line. The findings indicate anti-inflammatory activity in OPML, supporting a mechanistic role of SLPI in OSCC progression and suggesting its potential for preventative treatment of at-risk oral lesions. Collectively, our results show for the first time the potential for SLPI as a mechanism-based, non-invasive biomarker of oral cancer progression with potential in preventive treatment.

Szablewski V, Laurent-Roussel S, Rethers L, et al.
Atypical fibrous histiocytoma of the skin with CD30 and p80/ALK1 positivity and ALK gene rearrangement.
J Cutan Pathol. 2014; 41(9):715-9 [PubMed] Related Publications
We report the case of a two patients who presented with a solitary, asymptomatic, angiomatoid nodule on the right thigh. Histopathological finding showed a poorly circumscribed lesion, located in the dermis. The morphological aspect strongly suggested the diagnosis of atypical fibrous histiocytoma (AFH), but surprisingly, the neoplastic cells were diffusely CD30+, with a membrane staining devoid of paranuclear dot. The lesions were tested for p80/ALK1 expression. Surprisingly, we found a diffuse cytoplasmic positivity. Interestingly, using break-apart fluorescent in situ hybridization (FISH), we evidenced an ALK rearrangement in nearly 50% of the neoplastic cells. The expression of CD30 and ALK1 with ALK gene rearrangement raised the possibility of three diagnoses: a primary cutaneous anaplastic large cell lymphoma (ALCL), a cutaneous inflammatory myofibroblastic tumor (IMT), an AFH of the skin associated with ALK gene rearrangement and CD30 positivity. The three hypotheses were discussed and finally, although p80/ALK1 expression and cytogenetic abnormalities in fibrous histiocytoma (FH) are not yet reported to the best of our knowledge, we favored the diagnosis of AFH.

Varol N, Konac E, Onen IH, et al.
The epigenetically regulated effects of Wnt antagonists on the expression of genes in the apoptosis pathway in human bladder cancer cell line (T24).
DNA Cell Biol. 2014; 33(7):408-17 [PubMed] Related Publications
The epigenetic suppression of Wnt antagonists (sFRPs, DKKs, and WIF-1) causes the activation of both β-catenin and target genes, which play an important role in cell proliferation, metastasis, and angiogenesis. This study is aimed to investigate, on transcriptional and protein levels, the synergic effects of unaccompanied and/or combined use of 5-aza-2'-deoxycytidine (DAC, 5-aza-dC), trichostatin A (TSA), and gemcitabine+cisplatin chemotherapeutic agents on the apoptotic pathway of human bladder cancer cell line T24. The anti-tumor effects of gemcitabine (0-500 nM), cisplatin (0-10 μM), DAC (10 μM), and TSA (300 nM) alone and/or together on T24 cells were determined by WST-1. ELISA method was used to analyze the effects of unaccompanied and combined use of gemcitabine+cisplatin, DAC, and TSA on cell proliferation and determine the cytotoxic and apoptotic dosages at the level of H3 histone acetylation. Methylation-specific PCR was used to evaluate methylation profiles of Wnt antagonist gene (WIF-1). In the case of unaccompanied and/or combined use of specified drugs, the variations in the expression levels of CTNNB1, GSK3β, c-MYC, CCND1, CASP-3, CASP-8, CASP-9, BCL2L1, and WIF-1 genes were determined by quantitative real-time PCR. Our results indicate that through inhibition of DNA methylation, expression of β-catenin and Wnt antagonist re-activation and expressions of canonical Wnt/β-catenin pathway target genes, c-myc and cyclin D1 (CCND1), have decreased. In addition, DAC, TSA, and gemcitabine+cisplatin combination caused an increase in GSK3β mRNA levels, which in turn significantly decreased CCND1 mRNA levels. Moreover, BCL2L1, an anti-apoptotic gene, was downregulated significantly. Meanwhile, both CASP-3 mRNA and active caspase-3 protein levels increased with respect to control (p<0.01). The results revealed that use of quadruplicate gemcitabine+cisplatin+DAC+TSA combination led to a reduced inhibition of canonical Wnt/β-catenin pathway and reduced cell proliferation. Our findings may offer a new approach to consider in the treatment of bladder cancer.

Hutarew G, Hauser-Kronberger C, Strasser F, et al.
Immunohistochemistry as a screening tool for ALK rearrangement in NSCLC: evaluation of five different ALK antibody clones and ALK FISH.
Histopathology. 2014; 65(3):398-407 [PubMed] Related Publications
AIMS: ALK FISH analysis is used as the reference standard to demonstrate ALK rearrangements, which qualify patients with pulmonary adenocarcinomas for therapy with ALK inhibitors. The aim of this study was to find screening ALK antibody clones with the best positive and best negative percentage agreement with ALK FISH.
METHODS AND RESULTS: Three hundred and three pulmonary adenocarcinomas were evaluated with ALK FISH and stained with five ALK antibody clones (5A4; D5F3; ALK1; ALK01; SP8) with standardized detection systems. D5F3 was additionally assessed using the OptiView enhanced detection and amplification system. ALK FISH found 14 cases (4.6%) that harboured ALK rearrangements. These stained at all intensities for D5F3 and 5A4. To identify rearranged cases among stained cases, we subsequently analysed all immunohistochemically positive cases with ALK FISH.
CONCLUSIONS: D5F3 with OptiView exclusively stained rearranged cases with strong intensity, without a single false-positive or false-negative case. The number of subsequent ALK FISH analyses required would have decreased from 303 to 14 cases (-95.4%), reducing significantly the time, work and costs without any loss of diagnostic quality and accuracy.

Mackinnon AC, Luevano A, de Araujo LC, et al.
Cribriform adenocarcinoma of the lung: clinicopathologic, immunohistochemical, and molecular analysis of 15 cases of a distinctive morphologic subtype of lung adenocarcinoma.
Mod Pathol. 2014; 27(8):1063-72 [PubMed] Related Publications
Lung adenocarcinoma is characterized by marked heterogeneity and may be composed of an admixture of histologic growth patterns, including acinar, papillary, solid, and lepidic (bronchioloalveolar). Tumors displaying a prominent or predominant cribriform architecture are rare and most often confused for metastases from other organs. We report the clinical, histologic, immunohistochemical, and molecular features in 15 primary lung adenocarcinomas with a predominant cribriform histology. All patients were adults between 30 and 80 years of age (median: 64), and all but one reported a history of heavy cigarette smoking. All cases showed a predominant (>70%) cribriform architecture that resembled a variety of tumors arising in other organs, including breast, prostate, ovary, pancreas, uterus, colon, and thyroid. Immunohistochemical stains showed a phenotype consistent with a primary lung tumor (ie, TTF1+/CK7+), with negative results for other markers. Molecular analysis in six cases showed that none harbored an EGFR-activating mutation. KRAS mutation was detected in one case, and an ALK1 and ROS1 gene rearrangement were each detected in an additional two cases. Cribriform adenocarcinomas of the lung represent a distinctive histologic subtype of lung cancer that may be morphologically difficult to differentiate from metastases with a predominant cribriform architecture.

Chu T, Teng J, Jiang L, et al.
Lung cancer-derived Dickkopf1 is associated with bone metastasis and the mechanism involves the inhibition of osteoblast differentiation.
Biochem Biophys Res Commun. 2014; 443(3):962-8 [PubMed] Related Publications
Wnt/β-catenin signaling and Dickkopf1 (DKK1) play important roles in the progression of lung cancer, which preferably metastasizes to skeleton. But the role of them in bone dissemination is poorly understood. This study aims to define the role of DKK1 in lung cancer bone metastases and investigate the underlying mechanism. Our results demonstrated that DKK1 over-expression was a frequent event in non-small-cell lung cancer (NSCLC) blood samples, and serous DKK1 level was much higher in bone metastatic NSCLC compared to non-bone metastatic NSCLC. We also found that conditioned medium from DKK1 over-expressing lung cancer cells inhibited the differentiation of osteoblast, determined by alkaline phosphatase activity and osteocalcin secretion, whereas the conditioned medium from DKK1 silencing lung cancer cells exhibited the opposite effects. Mechanistically, DKK1 reduced the level of β-catenin and RUNX2, as well as inhibiting the nuclear translocation of β-catenin. Taken together, these results suggested that lung cancer-produced DKK1 may be an important mechanistic link between NSCLC and bone metastases, and targeting DKK1 may be an effective method to treat bone metastase of NSCLC.

Ryan C, Mayer N, Cunningham J, et al.
Increased ALK1 copy number and renal cell carcinoma-a case report.
Virchows Arch. 2014; 464(2):241-5 [PubMed] Related Publications
There have been recent reports of a rare variant of renal cell carcinoma associated with upregulation of the anaplastic lymphoma kinase gene (ALK) arising as a consequence of chromosomal translocations. The tumours were described as having a characteristic morphology. Here, we describe a case with similar morphology characterised by eosinophilic cells, abundant intracytoplasmic lumina and scattered large ganglion-like tumour cells. There was focal staining for ALK demonstrated by immunohistochemistry. However, rather than exhibiting a chromosomal translocation involving ALK, the use of FISH and a break-apart probe demonstrated that there was increased copy number of intact 2p23, the chromosomal region containing the ALK gene. Furthermore, the use of comparative genomic hybridisation showed increase of the whole of chromosome 2 along with chromosomes 6 and 17. There was no evidence of loss of 3p nor of trisomy of 7 associated with clear cell and papillary carcinoma, respectively. We suggest that this demonstrates a novel mechanism of upregulation of ALK activity by increased copy number occurring during the development of a renal carcinoma with the characteristic ALK-associated morphology.

Gultekin KE, Yurdakonar MK, Yaman E, et al.
Effects of cisplatin and panobinostat on human mesothelial (Met-5A) and malignant pleural mesothelioma (MSTO-211H) cells.
Genet Mol Res. 2013; 12(4):5405-13 [PubMed] Related Publications
New therapeutic approaches are still needed for effective malignant pleural mesothelioma treatment. The use of classical chemotherapy agents in combination with newly developed molecules may shed light on new therapeutic approaches. We aimed to determine the efficacy of panobinostat, alone and in combination with cisplatin, on cell survival and mRNA expression of FOXO3A, CCND1, and CASP9 genes in both mesothelioma and healthy mesothelial cell lines. Cells were treated with 1-100 µM cisplatin and 25-1000 nM panobinostat. Methylthiazol tetrazolium assays were performed to determine cell viability. mRNA expression levels of genes were analyzed with quantitative real-time polymerase chain reaction. Cisplatin and panobinostat exposure of the cells for 24 h resulted in decreased cell survival. The combined treatment was found to be more effective. No significant changes were observed with respect to CCND1 expression after exposure to agents alone or in combination. However, agents in combination resulted in upregulation of FOXO3A and CASP9 in MSTO-211H cells. Gene expression levels were not affected by any agents in healthy cells. Use of cisplatin in combination with new chemotherapeutic agents may reduce the toxic effects of cisplatin in normal cells and result in more effective removal of tumor cells.

Jan Treda C, Fukuhara T, Suzuki T, et al.
Secretory leukocyte protease inhibitor modulates urethane-induced lung carcinogenesis.
Carcinogenesis. 2014; 35(4):896-904 [PubMed] Related Publications
Secretory leukocyte protease inhibitor (SLPI), 11.7 kDa serine protease inhibitor, is produced primarily in the respiratory tract, but it is often elevated in lung, head/neck and ovarian cancers. SLPI expression in relation to cancer progression, metastasis and invasion has been studied extensively in non-small cell lung cancer. However, the role of SLPI during the early stages of carcinogenesis remains unknown. We hypothesized that SLPI is required from the initiation and promotion to the progression of lung carcinogenesis. A skin allograft model using SLPI-knockout (SLPI-KO) mice and short hairpin RNA-treated cells was used to demonstrate that SLPI expression in tumor cells is crucial for tumor formation. Moreover, lung tumorigenesis induced by urethane, a chemical lung carcinogen, was significantly suppressed in SLPI-KO mice in association with decreased nuclear factor-kappaB (NF-κB) activity. SLPI deficiency also resulted in decreased cell numbers and decreased production of inflammatory cytokines in bronchoalveolar lavage fluids. The suppression of NF-κB activation in SLPI-KO mice was associated with lower expression of NF-κB-related survival genes and DNA repair genes. Our findings demonstrate that SLPI plays an important role from the initial stages of lung carcinogenesis to the progression of lung cancer in an NF-κB-dependent manner.

Tu B, Peng ZX, Fan QM, et al.
Osteosarcoma cells promote the production of pro-tumor cytokines in mesenchymal stem cells by inhibiting their osteogenic differentiation through the TGF-β/Smad2/3 pathway.
Exp Cell Res. 2014; 320(1):164-73 [PubMed] Related Publications
Mesenchymal stem cells (MSCs) are among the most important components of the osteosarcoma microenvironment and are reported to promote tumor progression. However, the means by which osteosarcoma cells modulate MSC behavior remains unclear. The aim of this study was to determine the effects of osteosarcoma cells on both the production of pro-tumor cytokines by mesenchymal stem cells (MSCs) and the osteogenic differentiation of MSCs. High level of transforming growth factor-β (TGF-β) was detected in three osteosarcoma cell lines. Conditioned media (CM) from the osteosarcoma cell lines Saos-2 and U2-OS were used to stimulate the cultured MSCs. We found that osteosarcoma cells promoted the production of IL-6 and VEGF in MSCs by inhibiting their osteogenic differentiation. Furthermore, TGF-β in tumor CM was proved to be an important factor. The TGF-β neutralizing antibody antagonized the effects induced by osteosarcoma CM. The inhibition of Smad2/3 by siRNA significantly decreased the production of IL-6 and VEGF in MSCs and induced their osteogenic differentiation. We also found that Smad2/3 enhanced the expression of β-catenin in MSCs by decreasing the level of Dickkopf-1 (DKK1). Although the inhibition of β-catenin did not affect the production of IL-6 or VEGF, or the gene expression of the early osteogenic markers Runx2 and ALP, it did enhance the gene expression of osteocalcin. Taken together, our data indicate that osteosarcoma cells secrete TGF-β to maintain the stemness of MSCs and promote the production of pro-tumor cytokines by these cells.

Li M, Gao J, Feng R, et al.
Generation of monoclonal antibody MS17-57 targeting secreted alkaline phosphatase ectopically expressed on the surface of gastrointestinal cancer cells.
PLoS One. 2013; 8(10):e77398 [PubMed] Article available free on PMC after 05/09/2015 Related Publications
BACKGROUND: Therapeutic antibody development is one of the fastest growing areas of the pharmaceutical industry. Generating high-quality monoclonal antibodies against a given therapeutic target is crucial for successful drug development. However, due to immune tolerance, making it difficult to generate antibodies using conventional approaches.
METHODOLOGY/FINDINGS: Mixed four human gastric cancer (GC) cell lines were used as the immunogen in A/J mice; sixteen highly positive hybridoma colonies were selected via fluorescence-activated cell sorting-high throughput screening (FACS-HTS) using a total of 20,000 colonies in sixty-seven 96-well plates against live cells (mixed human GC cells versus human PBMC controls). MS17-57 and control commercial Alkaline Phosphatase (ALP) mAbs were used to confirm the target antigens (Ags), which were identified as ALPs expressed on the GC cell surface through a combination of western blot, immunoprecipitation and mass spectrometry (MS). MS identified the Ags recognized by MS17-57 to be two variants of a secreted ALP, PALP and IALP (Placental and intestinal ALP). These proteins belong to a hydrolase enzyme family responsible for removing phosphate groups from many types of molecules. Immunofluorescence staining using MS17-57 demonstrated higher staining of gastrointestinal (GI) cancer tissues compared to normal GI tissues (P<0.03), and confirmed binding of MS17-57 to be restricted to a functional epitope expressed on the cancer cell surface. Proliferation assays using the PALP/IALP-expressing GC cell lines demonstrated that MS17-57 inhibited cell growth by 32 ± 8%. Transwell cell migration assays documented that MS17-57 can inhibit PALP/IALP-expressing GI cancer cell migration by 25 ± 5%. MS17-57 mAb inhibited tumor growth in nude mice.
CONCLUSIONS: Our findings indicate that PALP and IALP can be ectopically expressed on extracellular matrix of GI cancers, and that MS17-57 directed against PALP/IALP can inhibit GI cancer cells growth and migration in vitro and in vivo. This investigation provides an example of identification of cancer biomarkers representing promising therapeutic targets using mAb generated through a novel HTS technology.

Falci C, Gianesin K, Sergi G, et al.
Immune senescence and cancer in elderly patients: results from an exploratory study.
Exp Gerontol. 2013; 48(12):1436-42 [PubMed] Related Publications
BACKGROUND: The challenge of immune senescence has never been addressed in elderly cancer patients. This study compares the thymic output and peripheral blood telomere length in ≥70year old cancer patients.
PATIENTS AND METHODS: Fifty-two elderly cancer patients and 39 age-matched controls without personal history of cancer were enrolled. All patients underwent a Comprehensive Geriatric Assessment (CGA), from which a multidimensional prognostic index (MPI) score was calculated. Peripheral blood samples were studied for naïve and recent thymic emigrant (RTE) CD4(+) and CD8(+) cells by flow cytometry. T-cell receptor rearrangement excision circle (TREC) levels, telomere length and telomerase activity in peripheral blood cells were quantified by real-time PCR.
RESULTS: The percentages of CD8(+) naïve and CD8(+) RTE cells and TREC levels were significantly lower in cancer patients than in controls (p=0.003, p=0.004, p=0.031, respectively). Telomere lengths in peripheral blood cells were significantly shorter in cancer patients than in controls (p=0.046) and did not correlate with age in patients, whereas it did in controls (r=-0.354, p=0.031). Short telomere (≤median)/low TREC (≤median) profile was associated with higher risk of cancer (OR=3.68 [95% CI 1.22-11.11]; p=0.021). Neither unfitness on CGA nor MPI score were significantly related to thymic output or telomere length in either group.
CONCLUSIONS: Immune senescence is significantly worse in elderly cancer patients than in age-matched controls. The low thymic output and the shorter telomeres in peripheral blood cells of cancer patients may reflect a pre-existing condition which facilitates the onset of malignancies in elderly people.

Amm HM, Rollins DL, Ren C, et al.
Establishment and characterization of a primary calcifying epithelial odontogenic tumor cell population.
J Oral Pathol Med. 2014; 43(3):183-90 [PubMed] Article available free on PMC after 05/09/2015 Related Publications
UNLABELLED: Calcifying epithelial odontogenic tumors (CEOTs) are rare neoplasms derived from dental tissue with the unique characteristic of calcifying amyloid-like material.
OBJECTIVES: To establish primary CEOT epithelial-derived cell populations, investigate the expression of enamel matrix proteins (EMPs), and identify potential ameloblastin (AMBN) and patched 1 (PTCH1) gene alterations.
MATERIALS AND METHODS: A 28-year-old patient with a lesion of the posterior maxilla, radiographically characterized by a radiolucency with well-defined borders containing mixed radiopacities, agreed to participate with informed consent. The patient's biopsy confirmed the diagnosis of CEOT, and a small representative tumor fragment was ascertained for cell culture. Explant cultures were established and used to establish primary cell populations. These were analyzed for morphology, cell proliferation, mineralization activity, expression of epithelial-associated markers (qRT-PCR and immunocytochemistry), and gene mutations of AMBN or PTCH1. DNA was extracted from tumor cells and gene coding and exon-intron boundaries overlapping fragments amplified. PCR products were bidirectional DNA sequenced and compared against reference sequence.
RESULTS: A CEOT cell population was established and proliferated in culture and could be maintained for several passages. Expression of EMPs, cytokeratin 14 and 17, and patched (PTCH1), as well as ALP activity, was detected. These cells also had the ability to mineralize, similar to the primary tumor. Two AMBN alterations were identified in the sample: c.1323G>A/A441A (rs7680880) and c.1344*+111delA. Two single-nucleotide polymorphisms were identified in the PTCH1 gene.
CONCLUSIONS: Our data support the establishment of a CEOT-derived cell population, which expresses known epithelial-associated proteins.

Fradet A, Sorel H, Depalle B, et al.
A new murine model of osteoblastic/osteolytic lesions from human androgen-resistant prostate cancer.
PLoS One. 2013; 8(9):e75092 [PubMed] Article available free on PMC after 05/09/2015 Related Publications
BACKGROUND: Up to 80% of patients dying from prostate carcinoma have developed bone metastases that are incurable. Castration is commonly used to treat prostate cancer. Although the disease initially responds to androgen blockade strategies, it often becomes castration-resistant (CRPC for Castration Resistant Prostate Cancer). Most of the murine models of mixed lesions derived from prostate cancer cells are androgen sensitive. Thus, we established a new model of CRPC (androgen receptor (AR) negative) that causes mixed lesions in bone.
METHODS: PC3 and its derived new cell clone PC3c cells were directly injected into the tibiae of SCID male mice. Tumor growth was analyzed by radiography and histology. Direct effects of conditioned medium of both cell lines were tested on osteoclasts, osteoblasts and osteocytes.
RESULTS: We found that PC3c cells induced mixed lesions 10 weeks after intratibial injection. In vitro, PC3c conditioned medium was able to stimulate tartrate resistant acid phosphatase (TRAP)-positive osteoclasts. Osteoprotegerin (OPG) and endothelin-1 (ET1) were highly expressed by PC3c while dikkopf-1 (DKK1) expression was decreased. Finally, PC3c highly expressed bone associated markers osteopontin (OPN), Runx2, alkaline phosphatase (ALP), bone sialoprotein (BSP) and produced mineralized matrix in vitro in osteogenic conditions.
CONCLUSIONS: We have established a new CRPC cell line as a useful system for modeling human metastatic prostate cancer which presents the mixed phenotype of bone metastases that is commonly observed in prostate cancer patients with advanced disease. This model will help to understand androgen-independent mechanisms involved in the progression of prostate cancer in bone and provides a preclinical model for testing the effects of new treatments for bone metastases.

Lau CP, Huang L, Wong KC, Kumta SM
Comparison of the anti-tumor effects of denosumab and zoledronic acid on the neoplastic stromal cells of giant cell tumor of bone.
Connect Tissue Res. 2013; 54(6):439-49 [PubMed] Related Publications
Denosumab and Zoledronic acid (ZOL) are two antiresorptive drugs currently in use for treating osteoporosis. They have different mechanisms of action but both have been shown to delay the onset of skeletal-related events in patients with giant cell tumor of bone (GCT). However, the anti-tumor mechanisms of denosumab on the neoplastic GCT stromal cells remain unknown. In this study, we focused on the direct effects of denosumab on the neoplastic GCT stromal cells and compared with ZOL. The microscopic view demonstrated a reduced cell growth in ZOL-treated but not in denosumab-treated GCT stromal cells. ZOL was found to exhibit a dose-dependent inhibition in cell growth in all GCT stromal cell lines tested and cause apoptosis in two out of three cell lines. In contrast, denosumab only exerted a minimal inhibitory effect in one cell line and did not induce any apoptosis. ZOL significantly inhibited the mRNA expression of receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG) in two GCT stromal cell lines whereas their protein levels remained unchanged. On the contrary, denosumab did not regulate RANKL and OPG expression at both mRNA and protein levels. Moreover, the protein expression of Macrophage Colony-Stimulating Factor (M-CSF), Alkaline Phosphatase (ALP), and Collagen α1 Type I were not regulated by denosumab and ZOL either. Our findings provide new insights in the anti-tumor effect of denosumab on GCT stromal cells and raise a concern that tumor recurrence may occur after the withdrawal of the drug.

Quabius ES, Möller P, Haag J, et al.
The role of the antileukoprotease SLPI in smoking-induced human papillomavirus-independent head and neck squamous cell carcinomas.
Int J Cancer. 2014; 134(6):1323-34 [PubMed] Related Publications
Recently, we showed that increased SLPI levels prevent human papillomavirus (HPV) infections and metastasis in smoking-induced, non-HPV-driven head and neck squamous cell carcinoma (HNSCC). Here, we focus on the role of SLPI in non-HPV-driven HNSCC, investigating tumor tissue and non-neoplastic mucosa from the same patients and from non-HNSCC patients. Gene and protein expression of SLPI and gene expression of annexin 2 (a SLPI receptor), nicotine receptor (α7AChR) and arylhydrocarbon receptor (AhR) were analyzed in HNSCC patients (20 smokers; 16 nonsmokers). SLPI-results were correlated with the patients' HPV status. Non-neoplastic mucosa of HNSCC patients and normal mucosa from non-HNSCC individuals (18 smokers; 20 nonsmokers) was analyzed for the same parameters. Tissue of the inferior turbinate (n = 10) was incubated with nicotine for analysis of the same genes. SLPI gene expression in tumor tissue was 109.26 ± 23.08 times higher in smokers versus nonsmokers. Non-neoplastic mucosa of smokers showed also higher SLPI gene expression (10.49 ± 1.89-fold non-HNSCC; 18.02 ± 3.93-fold HNSCC patients). Annexin 2 gene expression was also increased in smokers. SLPI data were corroborated by immunohistochemistry. A nicotine dependent correlation between SLPI and annexin 2 gene expression (r(2) = 0.15, p < 0.001) was shown ex vivo. Nicotine and smoking increased α7AChR and AhR gene expression. Five patients, showing no/low SLPI expression, were HPV16-positive. A significant correlation between smoking and SLPI expression in tumors and to our knowledge for the first time in mucosa of HNSCC and non-HNSCC patients was established. Together with the finding that all patients with HPV infection showed no/low SLPI expression, these data support our intriguing hypothesis that smoking induced upregulated SLPI prevents HPV infections.

Zhao S, Sun HZ, Zhu ST, et al.
Effects of parafibromin expression on the phenotypes and relevant mechanisms in the DLD-1 colon carcinoma cell line.
Asian Pac J Cancer Prev. 2013; 14(7):4249-54 [PubMed] Related Publications
BACKGROUND: Parafibromin is a protein encoded by the HRPT2 (hyperparathyroidism 2) oncosuppressor gene and its down-regulated expression is involved in pathogenesis of parathyroid, breast, gastric and colorectal carcinomas. This study aimed to clarify the effects of parafibromin expression on the phenotypes and relevant mechanisms of DLD-1 colon carcinoma cells.
METHODS: DLD-1 cells transfected with a parafibromin-expressing plasmid were subjected to examination of phenotype, including proliferation, differentiation, apoptosis, migration and invasion. Phenotype-related proteins were measured by Western blot. Parafibromin and ki-67 expression was detected by immunohistochemistry on tissue microarrays.
RESULTS: The transfectants showed higher proliferation by CCK-8, better differentiation by electron microscopy and ALP activity and more apoptotic resistance to cisplatin by DNA fragmentation than controls. There was no difference in early apoptosis by annexin V, capase-3 activity, migration and invasion between DLD-1 cells and their transfectants. Ectopic parafibromin expression resulted in down-regulated expression of smad4, MEKK, GRP94, GRP78, GSK3β-ser9, and Caspase-9. However, no difference was detectable in caspase-12 and -8 expression. A positive relationship was noted between parafibromin and ki-67 expression in colorectal carcinoma.
CONCLUSIONS: Parafibromin overexpression could promote cell proliferation, apoptotic resistance, and differentiation of DLD-1 cells.

Wang W, Baggerly KA, Knudsen S, et al.
Independent validation of a model using cell line chemosensitivity to predict response to therapy.
J Natl Cancer Inst. 2013; 105(17):1284-91 [PubMed] Article available free on PMC after 05/09/2015 Related Publications
BACKGROUND: Methods using cell line microarray and drug sensitivity data to predict patients' chemotherapy response are appealing, but groups may be reluctant to release details to preserve intellectual property. Here we describe a case study to validate predictions while treating the methods as a "black box."
METHODS: Medical Prognosis Institute (MPI) constructed cell-line-derived sensitivity scores (SSs) and combined scores (CSs) that incorporate clinical variables. MD Anderson researchers evaluated their predictions. We searched the Gene Expression Omnibus (GEO) to identify validation datasets, and we performed statistical evaluation of the agreement between prediction and clinical observation.
RESULTS: We identified 3 suitable datasets: GSE16446 (n = 120; binary outcome), GSE17920 (n = 130; binary outcome), and GSE10255 (n = 161; continuous and time-to-event outcomes). The SS was statistically significantly associated with primary treatment responses for all studies (GSE16446: P = .02; GSE17920: P = .02; GSE10255: P = .02). Dichotomized SSs performed no better than chance for GSE16446 and GSE17920, and categorized SSs did not predict disease-free survival (GSE10255). SSs sometimes improved on predictions using clinical variables (GSE16446: P = .05; GSE17920: P = .31; GSE10255: P = .045), but gains were limited (95% confidence intervals for GSE16446 and GSE17920 include 0). The CS did not predict treatment response for GSE16446 (P = .55), but it did for GSE17920 (P < .001). Coefficients of clinical variables provided by MPI for CSs agree with estimates for GSE17920 better than estimates for GSE16446.
CONCLUSIONS: Model predictions were better than chance in all three datasets. However, these scores added little to existing clinical predictors; statistically significant contributions were likely to be too small to change clinical practice. These findings suggest that discovering better predictors will require both cell line data and a clinical training dataset of patient samples.

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