Ubiquitin C-terminal hydrolase-L1 has prognostic relevance and is a therapeutic target for high-grade neuroendocrine lung cancers

Yoshihisa Shimada, Yujin Kudo, Sachio Maehara, Jun Matsubayashi, Yoichi Otaki, Naohiro Kajiwara, Tatsuo Ohira, John D. Minna, Norihiko Ikeda

Research output: Contribution to journalArticle

Abstract

High-grade neuroendocrine lung cancer (HGNEC), which includes small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) of the lung is a rapidly proliferating, aggressive form of lung cancer. The initial standard chemotherapeutic regimens of platinum doublets are recommended for SCLC and have been frequently used for LCNEC. However, there are currently no molecularly targeted agents with proven clinical benefit for this disease. The deubiquitinating enzyme ubiquitin C-terminal hydrolase-L1 (UCHL1) is a neuroendocrine cell-specific product that is known as a potential oncogene in several types of cancer, but little is known about the biological function of UCHL1 and its therapeutic potential in HGNEC. In this study, we found that preclinical efficacy evoked by targeting UCHL1 was relevant to prognosis in HGNEC. UCHL1 was found to be expressed in HGNEC, particularly in cell lines and patient samples of SCLC, and the combined use of platinum doublets with selective UCHL1 inhibitors improved its therapeutic response in vitro. Immunohistochemical expression of UCHL1 was significantly associated with postoperative survival in patients with HGNEC and contributed towards distinguishing SCLC from LCNEC. Circulating extracellular vesicles (EV), including exosomes isolated from lung cancer cell lines and serum from early-stage HGNEC, were verified by electron microscopy and nanoparticle tracking analysis. Higher levels of UCHL1 mRNA in EV were found in the samples of patients with early-stage HGNEC than those with early-stage NSCLC and healthy donors’ EV. Taken together, UCHL1 may be a potential prognostic marker and a promising druggable target for HGNEC.

Original languageEnglish (US)
Pages (from-to)610-620
Number of pages11
JournalCancer Science
Volume111
Issue number2
DOIs
StatePublished - Feb 1 2020

Keywords

  • UCHL1
  • exosomes
  • extracellular vesicles
  • high-grade neuroendocrine carcinoma
  • large cell neuroendocrine carcinoma
  • small cell lung cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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