Expression of Notch1 and Numb in small cell lung cancer

Kikuchi, Hajime; Sakakibara‐Konishi, Jun; Furuta, Megumi; Yokouchi, Hiroshi; Nishihara, Hiroshi; Yamazaki, Shigeo; Uramoto, Hidetaka; Tanaka, Fumihiro; Harada, Masao; Akie, Kenji; Sugaya, Fumiko; Fujita, Yuka; Takamura, Kei; Kojima, Takao; Harada, Toshiyuki; Higuchi, Mitsunori; Honjo, Osamu; Minami, Yoshinori; Watanabe, Naomi; Oizumi, Satoshi; Suzuki, Hiroyuki; Ishida, Takashi; Dosaka‐Akita, Hirotoshi; Isobe, Hiroshi; Munakata, Mitsuru; Nishimura, Masaharu

doi:10.18632/oncotarget.14411

Cited by 21 publications

(18 citation statements)

References 25 publications

(36 reference statements)

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“…In this study, we showed that nuclear NOTCH1 expression was negatively correlated with malignancy status, this means that loss of nuclear NOTCH1 expression, the presumably active protein, might favor neoplastic progression from precursor cervical lesions (CIN) to cancer (ICC). Similar findings were recently observed in a study of small cell lung cancer, in which high NOTCH1 expression was an independent favorable prognostic factor [ 45 ].…”

Section: Discussionsupporting

confidence: 90%

Loss of nuclear NOTCH1, but not its negative regulator NUMB, is an independent predictor of cervical malignancy

et al. 2018

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The participation of NOTCH signaling in invasive cervical cancer (ICC) remains controversial since both tumor suppressive and oncogenic properties have been described. Additionally, the role of NUMB, a negative regulator of NOTCH, remains unclear in ICC. We aimed to investigate the role of NOTCH1 and NUMB expression and their localization in cervical intraepithelial neoplasia (CIN) and ICC samples. A total of 144 biopsies were obtained from the Instituto Nacional de Cancerología, México from 2004 to 2017, and were subjected to immunohistochemistry for NOTCH1 and NUMB. We found that nuclear NOTCH1 expression was more frequently found in CIN samples compared with ICC (77.55% vs. 15.79%, p = 0.001). NUMB was almost exclusively found in the nucleus of CIN samples (32.65% vs. 6.32%, p = 0.001). Cytoplasmic expression of NOTCH1 (44.21%) and NUMB (35.79%) was the most frequent localization in ICC. Multivariable-adjusted analysis showed that the loss of nuclear NOTCH1 expression was an independent predictor of malignancy (β = –3.428, 95% confidence interval [95% CI] = –5.127, –1.728, p = 0.001). In contrast, the association between cytoplasmic NUMB expression and cervical cancer was lost after adjusting for nuclear NOTCH1 expression (β = 2.074, 95% [CI] = –0.358, 4.506, P = 0.094). Additionally, patients with cytoplasmic NOTCH1 expression showed a borderline association with longer overall survival (OS) than those with nuclear NOTCH1 expression (P = 0.08). Our data suggest that the loss of nuclear NOTCH1 but not NUMB might be an independent predictor of malignancy in cervical cancer.

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Section: Discussionsupporting

confidence: 90%

Loss of nuclear NOTCH1, but not its negative regulator NUMB, is an independent predictor of cervical malignancy

et al. 2018

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“…Although DLL3 is a Notch ligand and ASCL1 is suppressed by Notch target genes , there were no correlations between DLL3 or ASCL1 expression with Notch1 expression using the tumor specimens from our previous study (supplemental online Fig. 1) . Moreover, we obtained data regarding the expression of neuroendocrine (NE)‐specific proteins, including chromogranin A, synaptophysin, and CD56, based on pathological reports of each surgical specimen when possible.…”

Section: Resultsmentioning

confidence: 99%

“…DLL3 and ASCL1 scoring was only assessed in histologically SCLC cells, not in cancer cells histologically characterized as squamous cell carcinoma, adenocarcinoma, or large cell carcinoma components. Notch1 protein expression from previously reported data was used for analysis .…”

Section: Methodsmentioning

confidence: 99%

Analysis of DLL3 and ASCL1 in Surgically Resected Small Cell Lung Cancer (HOT1702)

et al. 2019

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Background Delta‐like protein 3 (DLL3) is a Notch ligand that has an important role in the tumorigenesis of small cell lung cancer (SCLC). Recently, rovalpituzumab tesirine (Rova‐T), a DLL3‐targeted antibody‐drug conjugate, has been developed for treating SCLC. DLL3 is a transcriptional target of the achaete‐scute homolog‐1 (ASCL1) transcription factor, which is involved in pulmonary neuroendocrine cell development. However, the relationship between DLL3 and/or ASCL1 expression and the clinical features of SCLC remains unknown, especially for early‐stage resected SCLC. This study aimed to investigate the expression of DLL3 and ASCL1 in resected SCLC samples using immunohistochemical analysis. Materials and Methods We collected 95 surgically resected SCLC samples, which were formalin fixed and paraffin embedded. Immunohistochemistry staining was performed to investigate the correlation between the expression of either DLL3 or ASCL1 and clinicopathological features of study patients. Results Seventy‐seven (83%) of 93 immunohistochemically evaluable samples were positive for DLL3 (expression in ≥1% of tumor cells), and DLL3‐high expression (≥75%) was observed in 44 samples (47%). Sixty‐one (64%) of 95 samples were positive for ASCL1 (expression in ≥5% of tumor cells). A positive correlation was observed between DLL3 and ASCL1 expression. DLL3 and ASCL1 expression were not associated with survival in SCLC patients. DLL3 was more prevalent in patients with advanced clinical disease. Conclusion DLL3 and ASCL1 were highly expressed in patients with surgically resected SCLC. DLL3 and ASCL1 may be targets for the treatment of SCLC. Implications for Practice This article examines the relationship between delta‐like protein 3 (DLL3) and achaete‐scute homolog‐1 (ASCL1) protein expression with the clinical features of 95 surgically resected small cell lung cancer (SCLC). DLL3 is attracting attention because rovalpituzumab tesirine (Rova‐T), a DLL3‐targeted antibody‐drug conjugate, was developed recently. DLL3 and ASCL1 were highly expressed in patients with surgically resected SCLC. DLL3 and ASCL1 may be targets for the treatment of early‐stage SCLC, including with Rova‐T.

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“…IHC was performed as previous described [ 37 ]. Numb NICD1 and NICD4 were detected by IHC with a rabbit polyclonal anti-Numb antibody (1:500 dilution; ab14140, Abcam, Cambridge, UK) a rabbit monoclonal anti-NICD1 antibody (1:400 dilution; #3608, Cell Signaling, Danvers, MA, USA) and a rabbit polyclonal anti-NICD4 antibody (1:200 dilation; ab199295, Abcam, Cambridge, UK).…”

Section: Methodsmentioning

confidence: 99%

Numb has distinct function in lung adenocarcinoma and squamous cell carcinoma

et al. 2018

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Some reports suggest that Numb is a potential tumor suppressor. However, its role in non-small cell lung cancer remains unclear. Non-small cell lung cancer comprises two major histological subtypes, adenocarcinoma and squamous cell carcinoma. To investigate the role of Numb in tumorigenesis of lung adenocarcinoma and squamous cell carcinoma, we firstly performed loss-of-function and gain-of-function assays. Moreover, Numb expression was investigated in surgically resected lung adenocarcinoma and squamous cell carcinoma tissues by immunohistochemistry and correlations with prognosis were analyzed. Numb suppressed the proliferation, migration, and invasion of adenocarcinoma cells and inhibited Notch signaling and epithelial-mesenchymal transition in vitro. Numb overexpression also inhibited subcutaneous adenocarcinoma tumor growth. In contrast, Numb promoted the proliferation, migration, and invasion of squamous cell carcinoma cells, but did not induce any consistent changes in Notch signaling. High Numb expression was associated with favorable prognosis in patients with lung adenocarcinoma, but not in those with squamous cell carcinoma. Collectively, our data demonstrate that Numb plays distinct roles in lung adenocarcinoma and squamous cell carcinoma. In lung adenocarcinoma, Numb impairs tumor growth and inhibits the Notch pathway and epithelial-mesenchymal transition, whereas in lung squamous cell carcinoma it may promote proliferation.

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Expression of Notch1 and Numb in small cell lung cancer

Cited by 21 publications

References 25 publications

Loss of nuclear NOTCH1, but not its negative regulator NUMB, is an independent predictor of cervical malignancy

Loss of nuclear NOTCH1, but not its negative regulator NUMB, is an independent predictor of cervical malignancy

Analysis of DLL3 and ASCL1 in Surgically Resected Small Cell Lung Cancer (HOT1702)

Numb has distinct function in lung adenocarcinoma and squamous cell carcinoma

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