Abstract
Delta-like homolog 1 (DLK1) regulates noncanonical Notch signaling pathway as ligand. DLK1 was abnormally expressed in a variety of tumors, affecting tumorigenesis and developments. The biological function of DLK1 toward cell proliferation and signaling activation was controversial across different cell types. Two currently known isoforms of DLK1, which are membrane-tethered isoform and soluble isoform, are believed to be the key of DLK1 dual behaviors. While these isoforms are not enough to explain the phenomena, our observations offer the possibility of a third isoform of DLK1. In the present study, we verified the nuclear localization of DLK1 in lung cancer cells. The nuclear localized DLK1 was observed in 107 of 351 non-small cell lung cancer (NSCLC) samples and was associated with tissue differentiation and tumor size. Through co-immunoprecipitation (co-IP) combined mass spectrometry (MS), we identified nuclear receptor corepressor 1 (NCOR1) as DLK1’s novel interaction protein and confirmed their interaction in nuclear. We analyzed the expression of NCOR1 in two independent cohorts and demonstrated that NCOR1 is a tumor suppressor and has prognosis potential in lung squamous carcinomas. At last, we analyzed the colocalization of DLK1 and NCOR1 in 147 NSCLC samples by immunohistochemistry (IHC). The result indicated NCOR1 might participate with nuclear localized DLK1 in regulating cell differentiation.
Highlights
Lung cancer is the cancer with the highest incidence and mortality rates for both genders worldwide [1,2]
We investigated the correlation of Delta-like homolog 1 (DLK1) expression and the clinical feature of the patients, including patients’ age, gender
To determine the role of nuclear receptor corepressor 1 (NCOR1) in non-small cell lung cancer (NSCLC) and explore the coordination with DLK1, we examined the expression of NCOR1 on the same batch of tumor tissue microarray (TMA) samples by IHC
Summary
Lung cancer is the cancer with the highest incidence and mortality rates for both genders worldwide [1,2]. Our precious studies based on mRNA micro-array analysis revealed that Delta-like homolog 1 (DLK1) was up-regulated expressed in human lung squamous cell carcinoma (SCC/LUSC) [3]. DLK1, in short for the Delta-like 1 homolog, named as the pre-adipocyte factor 1 (Pref-1) [4] or fetal antigen-1 (FA1) [5], is an essential and widely expressed protein during human embryonic period. We found that up-regulated DLK1 expression is associated with lung cancer cell invasion through activating Notch signaling [7]. DLK1 was found aberrantly expressed in other human cancers, including hepatocellular carcinoma (HCC) [8], breast cancer (BC) [9], acute myeloid leukemia (AML) [10] and so on.
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