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Open Access Research article

PTPRZ1 regulates calmodulin phosphorylation and tumor progression in small-cell lung carcinoma

Hideki Makinoshima12, Genichiro Ishii1, Motohiro Kojima1, Satoshi Fujii1, Youichi Higuchi23, Takeshi Kuwata1 and Atsushi Ochiai13*

Author Affiliations

1 Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan

2 Research Resident, Foundation for Promotion of Cancer Research, Chuuou-ku 5-1-1 Tsukiji, Tokyo, 104-0045, Japan

3 Laboratory of Cancer Biology, Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan

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BMC Cancer 2012, 12:537  doi:10.1186/1471-2407-12-537

Published: 21 November 2012

Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

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.

Keywords:
Small cell lung carcinoma (SCLC); Protein tyrosine phosphatase (PTP); Protein tyrosine phosphatase receptor Z1 (PTPRZ1); NETs (Neuroendocrine tumors); Pleiotrophin (PTN); Calmodulin (CaM)