Abstract
BackgroundInsulinoma associated-1 (INSM1) gene is expressed exclusively in early embryonic neuroendocrine tissues, but has been found highly re-activated in most of the neuroendocrine tumors including small cell lung carcinoma.MethodsIn order to elucidate the functional effects of INSM1 in normal lung development, we used a conditional lung-specific INSM1 transgenic mouse model. Transgenic (Tet-on system) CMV-INSM1 responder mice were bred with the lung-specific, club cell secretory protein (CCSP) promoter-rtTA activator mice to produce bi-transgenic progeny carrying both alleles, CCSP-rtTA and Tet-on-INSM1. Mice were fed with doxycycline containing food at the initial mating day to the postnatal day 21. Lung samples were collected at embryonic day 17.5, newborn, and postnatal day 21 for analyses.ResultsNorthern blot, RT-PCR, and immunohistochemical analyses revealed that doxycycline induced respiratory epithelium-specific INSM1 expression in bi-transgenic mice. Samples from postnatal day 21 mice revealed a larger lung size in the bi-transgenic mouse as compared to the single-transgenic or wild-type littermates. The histopathology results showed that the alveolar space in the bi-transgenic mice were 4 times larger than those in the single transgenic or wild-type littermates. In contrast, the size was not significantly different in the lungs collected at E17.5 or newborn among the bi-transgenic, single transgenic, or wild type mice. The respiratory epithelium with INSM1 ectopic expression suppressed cyclin D1 signal. Further in vitro studies revealed that the ectopic expression of INSM1 suppresses cyclin D1 expression and delays cell cycle progression.ConclusionThe current study suggests that CCSP promoter-driven INSM1 ectopic expression impairs normal lung development especially in postnatal alveologenesis.
Highlights
Insulinoma associated-1 (INSM1) gene is expressed exclusively in early embryonic neuroendocrine tissues, but has been found highly re-activated in most of the neuroendocrine tumors including small cell lung carcinoma
INSM1 is a sensitive small cell lung cancer marker Small cell lung cancer tumors are derived from pulmonary NE cells (PNECs), their antigenic profile coincides with that of NE cells
The expression pattern of INSM1 in NE lung cancer is consistent with the previous Northern blot analysis that revealed INSM1 mRNA is highly expressed in nearly 100 % of small cell lung carcinomas (SCLC) cell lines but not in normal adult lung tissues [6, 7]
Summary
Insulinoma associated-1 (INSM1) gene is expressed exclusively in early embryonic neuroendocrine tissues, but has been found highly re-activated in most of the neuroendocrine tumors including small cell lung carcinoma. INSM1 gene is expressed exclusively during early embryonic NE development, but has been found highly reactivated in NE tumors [6]. INSM1 is a sensitive marker for NE differentiation in human lung tumors. In most of the lung cancer cells examined, INSM1 expression showed high concordance with the other specific NE markers, synatophysin, L-dopa decarboxylase, and chromogranin A [7, 8]. An aggressive type of NE tumor, small cell lung carcinoma (SCLC) accounts for approximately 10 to 15 % of all lung cancers. INSM1 can be detected at high levels in most of the SCLC cancer tissues [7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
