LAD is highly heterogeneous, and its level of differentiation varies considerably. Sometimes, different parts of the same tumor showed distinct characteristics. In this research, the status of Notch-1 expression was observed to be associated with clinical stage, histological subtypes and survival outcomes of LAD patients.
Notch-1 was first found to associate with hematological diseases, and its expression level increased in multiple myeloma, Hodgkin’s lymphoma, anaplastic large cell lymphoma and acute myeloid leukemia [13, 14]. Recently, Notch-1 was widely studied and reported to aberrantly express in malignant tumors [15–19]. It was considered as a highly controversial gene because of its complex biological functions. Some researchers demonstrated that the up-regulation of Notch receptors and ligands such as Notch-1 and Jagged-1 will probably predict relatively metastasis in lung cancer . Notwithstanding that high expression of Notch-1 in a subgroup of NSCLC cells might be reported as a poor prognostic factor , different people hold different views. Zheng et al. found that overexpression of Notch-1 could substantially cause A549, a typical LAD cell line, to obtain cell cycle arrest and may suppress the growth of cancer . Coincidentally, although Notch-1 may correlate with the prognosis of LAD patients in our study, its expression was also affected by other factors.
The binary properties of Notch-1 which behaves as either an oncogene or a tumor suppressor may possibly depend on the developmental stages or various histological types in LAD patients . Herein, in view of the multidisciplinary classification of LAD, our data revealed that expression of Notch-1 is significantly correlated with histopathological subtypes of LAD. Some subtypes were easily got stained while others, particularly in SPA, were almost in a certain appearance of negative. On this basis, the prognosis of different histological types indicated significantly differences. Therefore, Notch-1 could be regulated by various factors during the development of LAD. Although the histologic heterogeneity is exactly an underlying complexity, we still consider that Notch-1 could serve as a meaningful biomarker for LAD patients. Maybe the expression linking with the subtypes is the reason why it acts as a protect factor in patients outcomes. Better survival has already been corroborated in LPAs, APAs and PPAs than in SPAs or MPAs, even though our selected cases contain much more of the former three types than the after. Probably, that’s the explanation of the survival analysis results of Notch-1 which was not in conformity with other literatures.
Interestingly, our results showed that the component of Notch signaling pathway is activated in both normal human alveolar or bronchial epithelium and lung tumor samples. It is unexpectedly that the level of Notch-1 protein was downregulated in LAD cells or tissues. The most reasonable explanation is what has been documented that Notch-1 could be trigged by hypoxia. Hypoxia acts as one of the major stimuli, the tumor microenvironment dramatically enhance Notch signaling in the progression of lung cancer, as well as many other types of tumorigenesis . Expression levels of Notch signaling components in human lung cells, especially in primary bronchial epithelial and small airway epithelial, reflect observations in surgical specimens, yet lung tumor cell lines showed weakly positive, such as Notch-1. Chen’s results strengthen a strong nuclear staining for Notch-1 intracellular domain in lung epithelia, whereas adenocarcinoma samples manifested decreased NICD-1, even undetectable vision in some tumor areas. Nevertheless, hypoxia would dramatically activate the Notch signaling pathway in LAD cells, oxygen concertrations were contributed to regulate Notch activity in lung cancer . Hypoxia may not only maintain malignant phenotypes of tumor cells but also cause poor response to treatment. This suggested that the functions of Notch pathway components in human LADs might be greatly influenced by tumor microenvironment.
Recently, it has been widely accepted that the dysregulation of the Notch signaling pathway existed in a variety of human tumors. Lung cancer has been characterized by a wide range of histological types. The heterogeneity of lung cancer, especially in NSCLC, had appeared obviously. Sometimes, a single one tumor may concurrently contain both adenocarcinoma behavior and squamous carcinoma performances. The differentiation may from startlingly well differentiated to entirely undifferentiated at the same time. As a receptor of Notch signaling pathway, Notch-1 was recommended as a vital factor in growth and development of various tumors. Some drugs which targeting the Notch signaling pathway has been taken into the clinical trials, used in the treatment of Alzheimer's disease and solid tumors [24, 25]. Herein, our results demonstrated that the expression of Notch-1 was co-associated with histological types of LAD patients. Although Notch-1 could not be an independent prognostic factor, we propose that it would be a significant predictive indicator, which was used to differentiate histological type of LADs. Moreover, Notch-1 was actually a contradiction community. It could exert different biological functions which influenced by many unknown factors, and this need to be further studied.
All the possible reasons were verified by more and more researchers. The function of Notch-1 was also found to be required for tumor initiation via regulating P53 stability. The results of Licciulli implicated that Notch-1 was a pivotal effector in Kras-driven Lung adenocarcinoma and a critical P53 regulator at a posttranslational level . Of interest, just like Kluk detected NICD1 staining in 151 NSCLCs, none of them showed diffuse strong staining. Thus, activation of Notch-1 doesn’t appear to be common in some solid tumors .
Taken together, downregulation of Notch-1 might be correlated with LAD development. Although Notch-1 was not an independent prognostic factor, it could be used as a predictable biomarker to be detected in different pathological and histological subtypes in LAD patients. Also, LAD patients with positive Notch-1 expression tend to have a prolong survival time. On the other hand, Notch-1 expression was figured out to associate with histological subtypes of LAD, which had totally disparate outcomes. Although further certification was needed, we still believe that the multiple roles of Notch-1 in NSCLC biology as well as its complex mechanisms should be further investigated in future.