PTPRZ1 regulates calmodulin phosphorylation and tumor progression in small-cell lung carcinoma
© Makinoshima et al.; licensee BioMed Central Ltd. 2012
Received: 17 July 2012
Accepted: 15 November 2012
Published: 21 November 2012
Small-cell lung carcinoma (SCLC) is a neuroendocrine tumor subtype and comprises approximately 15% of lung cancers. Because SCLC is still a disease with a poor prognosis and limited treatment options, there is an urgent need to develop targeted molecular agents for this disease.
We screened 20 cell lines from a variety of pathological phenotypes established from different organs by RT-PCR. Paraffin-embedded tissue from 252 primary tumors was examined for PTPRZ1 expression using immunohistochemistry. shRNA mediated PTPRZ1 down-regulation was used to study impact on tyrosine phosphorylation and in vivo tumor progression in SCLC cell lines.
Here we show that PTPRZ1, a member of the protein tyrosine- phosphatase receptor (PTPR) family, is highly expressed in SCLC cell lines and specifically exists in human neuroendocrine tumor (NET) tissues. We also demonstrate that binding of the ligand of PTPRZ1, pleiotrophin (PTN), activates the PTN/PTPRZ1 signaling pathway to induce tyrosine phosphorylation of calmodulin (CaM) in SCLC cells, suggesting that PTPRZ1 is a regulator of tyrosine phosphorylation in SCLC cells. Furthermore, we found that PTPRZ1 actually has an important oncogenic role in tumor progression in the murine xenograft model.
PTPRZ1 was highly expressed in human NET tissues and PTPRZ1 is an oncogenic tyrosine phosphatase in SCLCs. These results imply that a new signaling pathway involving PTPRZ1 could be a feasible target for treatment of NETs.
KeywordsSmall cell lung carcinoma (SCLC) Protein tyrosine phosphatase (PTP) Protein tyrosine phosphatase receptor Z1 (PTPRZ1) NETs (Neuroendocrine tumors) Pleiotrophin (PTN) Calmodulin (CaM)
Neuroendocrine tumors (NETs) that includes small cell lung carcinomas (SCLC), large cell neuroendocrine carcinomas (LCNEC), pancreatic neuroendocrine tumors (PanNET), medullary thyroid carcinomas (MTC), pheochromocytomas, paragangliomas, and carcinoids [1–4]. As one of the most malignant NETs, SCLC comprises approximately 15% of lung cancer cases, and basic and clinical research efforts have translated little innovation in the treatment of this disease over the past 30 years . Although SCLC appears to be effectively controlled with first line chemotherapy because of its relative high sensitivity to chemotherapy and radiotherapy, most patients ultimately relapse and salvage chemotherapy is considered . To identify novel drug targets against SCLC, a greater understanding of the pathology of SCLC through molecular analysis is urgently needed.
Dissection of the signaling pathways that may be involved in the regulation of SCLC growth, for example via phosphorylation or dephosphorylation of critical proteins, may shed light on new approaches for tumor elimination. Protein tyrosine phosphorylation is tightly regulated by protein tyrosine-kinases (PTKs) and protein tyrosine-phosphatases (PTPs) [7, 8]. PTPs play an important role in the inhibition and control of growth as tumor suppressors, since aberrant tyrosine phosphorylation is a characteristic feature of cancer cells [7–9]. Indeed, PTPs expressed as cell surface receptors (PTPRs) have been reported to be inactivated by genetic mutations in human cancer [9, 10]. On the other hand, there is mounting evidence suggesting that several PTPRs also have oncogenic function .
PTPRZ1, as a member of the PTPR family, is a single-pass type I membrane protein with two cytoplasmic tyrosine phosphatase domains (D1 and D2), an alpha-carbonic anhydrase domain (CA), chondroitin sulfate proteoglycans (CS-PGs) and a fibronectin type-III domain (FNIII) . PTPRZ1 interacts with its ligand pleiotrophin (PTN), which is a secreted growth factor involved in angiogenesis and tumor growth [12, 13]. Upon binding, PTN inactivates the phosphatase activity of PTPRZ1, which leads to an increased tyrosine phosphorylation status of important signaling molecules such as β-catenin, Fyn and RhoGAP [14–18]. With regard to cancer, PTPRZ1 expression was dramatically induced by genetic amplification caused by chronic oxidative stress and hypoxic stress through HIF-2 alpha [14, 19] and several previous studies suggested that PTPRZ1 regulates cancer cell growth and cell migration [18, 20–24].
In this paper, we found that PTPRZ1 is highly expressed in SCLC cell lines and specifically exists in human NET tissues. We hypothesized that PTPRZ1 functions to regulate tyrosine phosphorylation in SCLC cells and has an important role for SCLC tumor progression. To test this idea, we investigated the ability of PTPRZ1 to regulate tyrosine phosphorylation and tumor progression using SCLC cell lines.
LN229 (glioblastoma, ATCC#CRL-2611), U87MG (glioblastoma/astrocytoma, ATCC#HTB-14), Hela (cervix ADCA, ATCC#CCL-2), Caco2 (colorectal ADCA, ATCC#HTB-37), DLD1 (colorectal ADCA, ATCC#CCL-221), HCT116 (colorectal ADCA, ATCC#CCL-247), SW480 (colorectal ADCA, ATCC#CCL-228), A549 (lung ADCA, ATCC#CCL-185), LNCaP (prostate ADCA, ATCC#CRL-1740), MCF7 (breast ADCA, ATCC#HTB-22), A431 (squamous cell carcinoma, ATCC#CRL-1555), NCI-H69 (SCLC, ATCC#HTB-119), NCI-H82 (SCLC, ATCC#HTB-175), NCI-H345 (SCLC, ATCC#HTB-180), NCI-H446 (SCLC, ATCC#HTB-171), NCI-H510A (SCLC, ATCC#HTB-184), NCI-H1436 (SCLC, ATCC#CRL-5871), and NCI-H1930 (SCLC, ATCC#CRL-5906) were originally purchased from ATCC and stocked in our Research Center. TE1 (esophagus squamous cell carcinoma), TE3 (esophagus squamous cell carcinoma), TE4 (esophagus squamous cell carcinoma), TE5 (esophagus squamous cell carcinoma), and TE10 (esophagus squamous cell carcinoma) were gifts from Dr. Sasaki (National Cancer Center Research Institute). SBC-3 (SCLC, #JCRB0818) was obtained from the JCRB and stocked in our Research Center. All cell lines were cultured in cell culture dishes (BD Biosciences) at 37°C and 5% carbon dioxide using RPMI 1640 (SIGMA), DMEM (SIGMA) supplemented with 10% fetal bovine serum (FBS, Nichirei Bioscience), or HITES Medium [25, 26] supplemented with penicillin/streptomycin (Invitrogen). For the PTN assay, 100 ng/ml of recombinant human pleiotrophin/PTN (R&D Systems #252-PL) was used.
Human cancer samples
Samples were obtained with informed consent from each individual, and the study was approved by the Ethics Committee of the National Cancer Center East Hospital. During the period from January 1992 to December 2010, a total of 252 patients who had primary tumors were treated at the National Cancer Center Hospital East, Chiba, Japan. All primary cancers with a pathologic diagnosis based on the classification schema of the WHO classification were reviewed, with 105 cases as adenocarcinoma (ADC), 61 as squamous cell carcinoma (SQCC) and 86 as neuroendocrine tumors (NETs). We used tissue microarray (TMA) to measure PTPRZ1 expression within lung tumors . Each case in which more than 80% of the cancer cells reacted positively for an antibody to PTPRZ1 was recorded as positive.
Antibodies used included anti-PTPRZ1 (SIGMA #015103) , anti-Phosphotyrosine, clone 4 G10 (Millipore #05-321), anti-Calmodulin (Santa Cruz sc-5537, Millipore #05-173, abcam ab45689), anti-phospho-Calmodulin (Santa Cruz Biotechnology sc-23760-R, Millipore #09-295) and anti-β-tublin (Cell Signaling #2146).
All immunohistochemical (IHC) analyses were performed on paraffin-embedded tissues obtained from the primary tumor in the surgical specimen. For all IHC analyses the surgically resected specimens were fixed in 10% formalin and embedded in paraffin for routine pathological examination. We prepared and used 5-μm-thick paraffin sections cut from a paraffin block containing histological findings that were representative of the tumor. The procedure for IHC was previously described [27, 28]. Antigen retrieval was performed in citrate buffer solution (pH 6.0). Endogenous peroxidase was blocked with 0.3% H2O2 in methanol for 15 min and all slides were heated to 95°C by exposure to microwave irradiation for 20 min and then cooled at room temperature (RT). Slides were washed in PBS and after a 1 h incubation at RT with the primary antibodies, the slides were incubated for 30 min with a labeled polymer EnVision TM+, Peroxidase–conjugated anti-Mouse or Rabbit (Dako, Tokyo, Japan). The chromogen used was 2% 3, 3′-diaminobenzidine (DAB) in 50 mM Tris-buffer (pH 7.6) containing 0.3% hydrogen.
RNA isolation and real-time RT–PCR
Cells were washed with PBS and total RNA from the cell lines was isolated with TRIzol Reagent (Invitrogen). Complementary DNA (cDNA) was synthesized using the PrimeScript® RT reagent Kit (TaKaRa, Japan). Real-time RT–PCR was carried out with specific primers and a Smart Cycler (Cepheid, Sunnyvale, CA, USA). Real-time fluorescence monitoring of the PCR products was performed with SYBR Green I fluorescent dye (TaKaRa). The levels of expression of specific genes are reported as ratios to the level of expression of GAPDH in the same master reaction. Synthesized primers were purchased from TaKaRa Bio with Primer Set ID given as PTPRZ1, 3′ (HA082543). GAPDH was used for normalization as control and the relative quantitation value compared to the calibrator for that target is expressed as 2-(Ct-Cc).
Western blotting was performed as described . After lentivirus infection with the vector for shLUC or shPTPRZ1, total cell lysate was prepared from cells cultured in complete medium. Primary antibodies were used at 1:1000 dilution and β-tubulin was used as loading control.
Expression of short hairpin RNA (shRNA)
Plasmid construction was carried out with Gateway system (Invitrogen) according to the manufacturer’s instructions. Cloning vectors were pDNOR221 (Invitrogen) and pENTR/U6 (Invitrogen). The lentiviruses were produced using 293FT cells (Invitrogen) transfected with pCAG-HIVgp, pCMV-VSV-G-RSV-Rev, and a lentivirus vector based on CSII-CMV-RfA-IRES2-Venus (Dr. Miyoshi, RIKEN BioResource Center) expressing shRNA with the sequence described below. Transfection was achieved using Lipofectamine 2000 reagent (Invitrogen) according to the manufacturer’s instructions. Lentivirus-containing medium was filtered through a 0.45 μm filter and used for transduction of target cells. The sequences and plasmid names were; shLUC: GTGCGCTGCTGGTGCCAAC (pGL3, firefly luciferase), shPTPRZ1_1: GCCTATAAATTGTGAGAGCTT (pHMA017), shPTPRZ1_2: GCTGCTTTAGATCCATTCATA (pHMA019), and shPTPRZ1_3: GGATGGCAAACTGACTGAT (pHMA022).
Cells were incubated with anti-PTPRZ1 antibody (SIGMA) and excess antibody was removed by washing with PBS containing 2% FBS. Polyclonal goat anti-rabbit immunoglobulin conjugated to Phycoerythrin (PE) (Jackson) was added as a secondary antibody. The cells were then washed with PBS and flow cytometric analysis was performed using a FACSCalibur and FACSAria (BD Biosciences).
All of experimental SCID mice were handled in accordance with institutional guidelines established by the Animal Care Committee of the National Cancer Center East Hospital. H69 and H1930 SCLC cells expressing shRNA were injected into the subcutaneous tissue of SCID mice (7–8 weeks of age, CLEA, Tokyo, Japan). Tumor volume was calculated as the product of a scaling factor of 0.52 and the tumor length, width, and height were measured every week. For IHC analysis, organs were obtained from mice at 5 or 8 weeks after injection and fixed in 10% formalin.
Standard Student’s t-test was used to determine the significance between non-targeting control and shPTPRZ1 experiments. Statistical correlation was carried out using χ2test for independence (2 × 2 contingency table). P < 0.05 was considered statistically significant.
PTPRZ1 is highly expressed in SCLC cell lines
PTPRZ1 is specifically expressed in human NET tissues
The IHC analysis of PTPRZ1 expression in human tumor tissues
Breast ductal ADCA
Pancreatic ductal ADCA
Thyroid papillary carcinoma
Squamous cell carcinoma (SQCC)
Neuroendocrine tumor (NET)
Medullary thyroid carcinoma
Chromaffin cell tumor
RNAi knockdown of PTPRZ1 in SCLC cell lines
PTN induced calmodulin tyrosine phosphorylation in SCLC cells
PTPRZ1 is required for the tyrosine phosphorylation of CaM induced by PTN
To verify that the addition of PTN facilitated CaM phosphorylation specifically through its receptor PTPRZ1, we utilized the H69 and H1930 cell lines in which shZ1 was used to knock down PTPRZ1 expression. Although PTN induced tyrosine phosphorylation of CaM in H69 cells that expressed the control shLUC, the ablation of PTPRZ impaired PTN-induced CaM tyrosine phosphorylation in cells that expressed either of the two shZ1 constructs (Figure 4C). We confirm that PTPRZ1 was indispensable for the PTN-induced p-CaM in H1930 cells (Figure 4D).
As the serum levels of PTN were elevated in most SCLC patients in comparison to healthy controls , we thought PTPRZ1 expression might be correlate with the expression of phosphorylated CaM. To assess whether PTPRZ1-CaM regulation also occurred in vivo in human tissue, we stained for CaM and p-CaM. Indeed we found that the expression of PTPRZ1 and p-CaM was statistically correlated in human lung NET tissues (Figure 4E). These data thus demonstrate that ablation of PTPRZ1 prevents PTN-stimulated tyrosine phosphorylation of CaM in PTN-stimulated SCLC cells; the data indicate that endogenous PTPRZ1 is required for PTN-stimulating tyrosine phosphorylation of CaM in SCLC cells.
PTPRZ1 regulates tumor progression of SCLC in xenograft model
Here we demonstrate that PTPRZ1 specifically exists in human NET tissues and PTPRZ1 has an important oncogenic role in the tumor progression of SCLC in the murine xenograft model. We also found that PTPRZ1 regulates the tyrosine phosphorylation of CaM in the response to PTN in SCLC cells. Our results indicate that the putative tumor suppressor family PTPR can support tumor progression and is required for the tyrosine phosphorylation of CaM. This study supports the idea that a new signaling pathway involving PTPRZ1 could be a feasible target for treatment of cancers. The combination of our cellular and xenograft model findings advocates for the future preclinical testing of antibody therapy or small molecule inhibitors of PTPRZ1 for the treatment of NETs and SCLC.
The linkage between oncogenic PTPRZ1 function and CaM phosphorylation is still unclear. Perez-Pinera and colleagues demonstrated that phosphorylation of Anaplastic lymphoma kinase (ALK) in PTN-stimulated cells is mediated through the PTN/PTPRZ1 signaling pathway , indicating that ALK might phosphorylate CaM. Further experiments are needed to address the possibility of PTN mediating its effects via ALK  in SCLC cells, the effects of PTN deletion on tumor growth, and the mechanism of PTN/PTPRZ1 autocrine regulation in NET cells. CaM can bind up to four calcium ions, and can undergo post-translational modifications such as phosphorylation, acetylation, methylation and proteolytic cleavage, each of which can potentially modulate its actions . A prior biochemical study showed that tyrosine phosphorylation increased the association of CaM with nitric oxide synthase (NOS) . Because nitric oxide (NO) and NOS are ubiquitous in malignant tumors and known to exert pro-tumor effects [37, 38], PTPRZ1 may regulate NO production in SCLC cells by changing the tyrosine phosphorylation status of CaM. Tumor cell-derived NO promotes tumor progression by induction of tumor-cell invasion, proliferation and the expression of angiogenic factors [37, 38]. Indeed a recent research article demonstrated that glioma stem cell proliferation and tumor growth are promoted by iNOS .
With regards to another aspect of its oncogenic role, PTPRZ1 has a huge extracellular domain consisting of a alpha-carbonic anhydrase domain (CA), chondroitin sulfate proteoglycans (CS-PGs), and a fibronectin type-III domain (FNIII). PTPRZ1 expression is dramatically induced by hypoxic stress through HIF-2α , suggesting that PTPRZ1 may have an important role under hypoxic conditions. Recently, Jeong’s research group reported that CA was dramatically up-regulated in human SCLC tissues by proteomic analysis . A possible speculation is that the CA domain of PTPRZ1 could have an important function for tumor progression of SCLC and further studies will be required to address this issue.
We found that PTPRZ1 has an important oncogenic role in tumor progression in the murine xenograft model of SCLCs. Moreover we demonstrate that the binding of PTPRZ1 to its ligand PTN inactivates phosphatase activity, resulting in tyrosine phosphorylation of CaM in human tumors. These results indicate that a new signaling pathway involving PTPRZ1 could be a feasible target for treatment of NETs.
Small cell lung carcinoma
Protein tyrosine phosphatase
Protein tyrosine phosphatase receptor Z1
Small Hairpin RNA.
We thank all Dr. Junichi Nitadori, Dr. Nao Atsumi, Ms. Hashimoto and Mr. Yanagi for outstanding technical supports and all of the Ochiai Lab members for support and discussions. We thank Dr. Phillip Wong for carefully reading the manuscript and providing critical comments. This work was supported by the Foundation for the Promotion of Cancer Research, 3rd-Term Comprehensive 10-Year Strategy for Cancer Control (AO, grant number: Section#2). This study was also supported by the KAKENHI Grant-in-Aid for Young Scientists (B) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (No. 24700990).
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