Keratinization of Lung Squamous Cell Carcinoma Is Associated with Poor Clinical Outcome

Abstract

BackgroundAlthough the World Health Organization (WHO) classification of lung squamous cell carcinoma (SCC) was revised in 2015, its clinical implications for lung SCC subsets remain unclear. We investigated whether the morphologic characteristics of lung SCC, including keratinization, were associated with clinical parameters and clinical outcome of patients.MethodsA total of 81 patients who underwent curative surgical resection of diagnosed lung SCC, were enrolled in this study. Attributes such as keratinization, tumor budding, single cell invasion, and nuclear size within the tumor, as well as immunohistochemistry of Bcl-xL and pS6 expressions, were evaluated.ResultsThe keratinizing and nonkeratinizing subtypes did not differ with respect to age, sex, TNM stage, and morphologic parameters such as nuclear diameter, tumor budding, and single cell invasion at the tumor edge. Most patients with the keratinizing subtype (98.0%) had a history of smoking, whereas the nonkeratinizing group had a relatively higher proportion of never-smokers relative to the keratinizing group (24.0% vs. 2.0%; p=0.008, chi-square test). Expression of pS6 (a surrogate marker of mammalian target of rapamycin complex 1 [mTORC1] signaling that regulates keratinocyte differentiation), and Bcl-xL (a key anti-apoptotic molecule that may inhibit keratinization), did not correlate significantly with the presence of keratinization. Patients with the keratinizing subtype had a significantly shorter overall survival (85.2 months vs. 135.7 months, p=0.010, log-rank test), and a multivariate analysis showed that keratinization was an independent, poor prognostic factor (hazard ratio, 2.389; 95% confidence interval, 1.090–5.233; p=0.030).ConclusionIn lung SCC, keratinization is associated with a poor prognosis, and might be associated with smoking.

Crosstalk between let-7a-5p and BCL-xL in the Initiation of Toxic Autophagy in Lung Cancer

“…We found that the expressions of BCL-xL and let-7a-5p were significantly elevated in lung adenocarcinoma compared with the healthy adjacent control, while there were no significant alterations between lung squamous cell carcinoma and the corresponding control, indicating that dysregulation of BCL-xL and let-7a-5p might only affect the pathogenesis of lung adenocarcinoma, but not lung squamous cell carcinoma. In line with studies previously published, the expression of BCL-xL was not correlated with keratinization, a specific morphologic characteristic that was generally used to indicate the poor clinical outcome of lung squamous cell carcinoma 35 . On the other hand, inhibition of the Bcl-2 family of anti-apoptotic proteins caused a dose-dependent decrease of viability and clonogenicity in A549 lung cancer cells, 36 and downregulation of BCL-xL expression by 25% using an aptamer-targeted BCL-xL shRNA delivery system induced 14% late apoptosis in A549 lung cancer cells 37 …”

Molecular Signature of Subtypes of Non-Small-Cell Lung Cancer by Large-Scale Transcriptional Profiling: Identification of Key Modules and Genes by Weighted Gene Co-Expression Network Analysis (WGCNA)

“…At an earlier stage, lung SCC is accompanied by epidermal keratinisation. Park et al [64] have provided ample evidence that keratinisation is a significantly poor prognosis factor in lung SCC. Tumour with keratinisation was also more frequently observed among patients with a history of smoking.…”

Deep computational analysis of human cancer and non-cancer tissues details dysregulation of eIF4F components and their interactions in human cancers

“…In contrast, those genes have modest positive correlations with EIF4G1, EIF4A1 and EIF4EBP1, but no correlation with EIF4E in lung tumors. Their biological functions are involved in keratinization (formation of cornified envelope) -a pathological process associated with tumor progression in lung squamous cell carcinoma (Park et al, 2017) -and cell cycle regulation. The strengthened correlations of "cluster one" genes in tumors suggest that EIF4F genes reinforce their regulation of biological pathways that benefit malignancy.…”