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. 2015 Feb 6:8:9.
doi: 10.1186/s13045-014-0104-2.

Notch1 phenotype and clinical stage progression in non-small cell lung cancer

Dat Nguyen  1 , Larry Rubinstein  2 , Naoko Takebe  3 , Lucio Miele  4 , Joseph E Tomaszewski  5 , Percy Ivy  6 , James H Doroshow  7 , Sherry X Yang  8
Affiliations

Notch1 phenotype and clinical stage progression in non-small cell lung cancer

Dat Nguyen et al. J Hematol Oncol. .

Abstract

Background: Notch1 transmembrane receptor is activated through ligand-binding- triggered proteolytic cleavages and, upon release, the intracellular domain (N1-ICD) translocates into the nucleus and modulates target gene transcriptions. Notch activation has been implicated in tumorigenesis in an increasing number of human malignancies including non-small cell lung cancer (NSCLC). However, Notch1 in distinct expression patterns and activation status with tumor progression remains to be defined in NSCLC.

Methods: Notch1 and activated Notch1, N1-ICD, were examined by immunohistochemistry in 58 cases of stage I to IV NSCLC tumors. Association between Notch1 or N1-ICD expression and clinicopathological factors was assessed via correlation coefficient r statistics. P-values are two-sided.

Results: Detectable tumor Notch1, predominantly localized to the membrane and cytoplasm, was observed in 29 cases (50%, 95% Blyth-Still-Casella confidence interval 37 - 63%). It was negatively associated with stage (r=- 0.43, P<0.001) and nodal status (r=- 0.33, P = 0.01), but not tumor size. In contrast, nuclear N1-ICD expression level was low and found in 12% of NSCLC patients, neither significantly associated with stage nor nodal status. Upon Notch1 activation in vitro, a mostly extra-nuclear staining was substantially turned into the nuclear signal in cancer cells.

Conclusions: Notch1 in the largely inactivated phenotype is inversely associated with clinical stage progression in NSCLC. Notch1, rather than activated N1-ICD, may be a context-dependent restrictive factor to nodal metastasis.

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Figures

Figure 1
Figure 1
Expression of Notch1, N1-ICD-V1754 and E-cadherin by Western blot and immunocytochemistry in cancer cells. Western blot analysis demonstrates specific bands of the respective proteins of Notch1, N1-ICD-V1754 and E-cadherin in MCF-7, NCI-H23 and NCI-H522 cells (A). Notch1 (a, c) and N1-ICD-V1754 (b, d) expression in formalin-fixed and paraffin-embedded NCI-H23 cells (B). Magnifications x600.
Figure 2
Figure 2
Confirmation of expression of Notch1, N1-ICD-V1754 and E-cadherin in additional NSCLC cells. Expression of Notch1, N1-ICD-V1754 and E-cadherin were analyzed using Western blot in NSCLC NCI-H358 and NCI-H322M cells (A). E-cadherin expression was examined by immunohistochemistry in NSCLC NCI-H358 and NCI H322M cell lines (B). Magnifications x600.
Figure 3
Figure 3
Representative staining patterns of Notch1, N1-ICD-V1754 and heterogeneous tumor cell proliferation (Ki67) in NSCLC tumor tissues. Notch1, N1-ICD-V1754 and Ki67 in a case of undifferentiated carcinoma of the lung, showing high level of membranous/cytoplasmic/nuclear Notch1 expression (A2), nuclear N1-ICD-V1754 (A3), and Ki67 labeling (A4). Notch1, N1-ICD-V1754 and Ki67 in a case of squamous cell carcinoma of the lung, displaying high level of cytoplasmic/membranous/nuclear Notch1staining (B2), heterogeneous N1-ICD-V1754 (B3), and Ki67 proliferation (B4). Notch1, N1-ICD-V1754 and Ki67 in a case of adenocarcinoma of the lung, exhibiting cytoplasmic/membranous Notch1 signal (C2) and some nuclear N1-ICD-V1754 staining on the right (C3), and Ki67 expression (C4). HE staining of undifferentiated carcinoma, squamous cell carcinoma and adenocarcinoma of the lung (A1, B1, and C1). Magnifications x200.
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