Subtypes Of Lung Squamous Cell Carcinoma Research Articles

Targeting ITGB4/SOX2-driven lung cancer stem cells using proteasome inhibitors

This study investigates the role of integrin β4 (ITGB4) and stemness-associated factor SOX2 in platinum resistance in lung squamous cell carcinoma (LUSC). The expression of SOX2 and ITGB4 is found to be high in all LUSC subtypes, but the impact of ITGB4 expression on overall patient survival varies by subtype. Cancer stem cells (CSCs) isolated from LUSC patients were found to be resistant to cisplatin, but knocking down ITGB4 or SOX2 sensitized them to cisplatin. Carfilzomib (CFZ) synergized with cisplatin and suppressed CSC growth by inhibiting ITGB4 and SOX2 expression. Additionally, CFZ was found to inhibit SOX2 expression epigenetically by inhibiting histone acetylation at the SOX2 promoter site. CFZ also suppressed the growth of SOX2-dependent small cell lung cancer cells invitro and invivo. The study highlights the unique function of CFZ as a transcriptional suppressor of SOX2, independent of its proteasome inhibitory function.

What’s the difference between lung adenocarcinoma and lung squamous cell carcinoma? Evidence from a retrospective analysis in a cohort of Chinese patients

BackgroundLung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) are the two most common subtypes of lung cancer. Previously, they were categorized into one histological subtype known as non-small cell lung cancer (NSCLC) and often treated similarly. However, increasing evidence suggested that LUAD and LUSC should be classified and treated as different cancers. But yet, detailed differences in clinical features between LUAD and LUSC have not been well described.MethodsA cohort of 142 Chinese patients with 111 LUAD and 31 LUSC cases were consecutively enrolled from April 2019 to October 2020 in Hunan Provincial People’s Hospital. The clinical features of the patients were retrospectively analyzed and compared in the terms of general information, clinicopathologic characteristics, imaging findings and laboratory data.ResultsIn comparison with LUAD, LUSC patients had a significantly higher proportion of males, smokers, drinkers, higher-stage cases. The mean tumor size in LUSC patients was significantly larger than that in LUAD patients. Compared with LUAD patients, more of patients with LUSC had cough, fever and abundant sputum symptoms. Besides that, more bacterial infections and fungal infections were found in LUSC patients than that in LUAD patients. Imaging data shows that ground-glass opacity and patchy shadows in radiological films were more frequent in LUAD patients than that in LUSC patients. In addition to initial laboratory data, LUSC patients had higher levels of leukocytes, platelets, and creatinine that of LUAD patients.ConclusionsTogether, these results suggested that there exist distinct differences between LUAD and LUSC subtypes; LUSC may be a more malignant type in comparison with LUAD. Our findings may have potential implications in clinical settings. However, further multicenter studies are needed to validate these findings in a larger sample size.

LINC00628 is differentially expressed between lung adenocarcinoma and squamous cell carcinoma and is associated with the prognosis of NSCLC.

Non-small cell lung cancer (NSCLC) remains the most frequent malignancy worldwide, and lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) represent two major subtypes. LINC00628 has been demonstrated to promote LUAD progression; however, its clinical role in NSCLC remains elusive. The aim of the present study was to analyze the expression of long intergenic non-protein coding RNA 628 (LINC00628) in NSCLC, including in the LUAD and LUSC subtypes. In addition, its roles in NSCLC development and prognosis were also examined. Data from The Cancer Genome Atlas (TCGA) database were first used to assess the expression and prognostic potential in both LUAD and LUSC, then LINC00628 expression in 128 NSCLC tissues was measured using reverse transcription-quantitative PCR. A receiver operating characteristic curve was used to assess the ability of LINC00628 to discriminate between patients with LUAD and LUSC. Kaplan-Meier curves were used to analyze the relationship between LINC00628 expression and the overall survival of patients. Cox regression analysis was used to explore the potential prognostic factors that might be independently associated with NSCLC overall survival. Both in silico and tissue analysis data indicated that the expression of LINC00628 was significantly upregulated in NSCLC tissue compared with matched normal controls (P<0.001). LINC00628 expression levels were also significantly higher in LUAD cases than in patients with LUSC (P<0.001). In addition, LINC00628 could discriminate LUAD from LUSC cases. The expression of LINC00628 was significantly associated with tumor size (P=0.013), histological type (P=0.009), lymph node metastasis (P=0.021) and TNM stage (P=0.008). Survival analysis based on data from both TCGA and patients included in the present study identified an association between LINC00628 and overall survival in LUAD, but this relationship was not observed in LUSC for TCGA data. Cox regression analysis demonstrated that high LINC00628 expression was associated with poor overall survival in patients with LUAD (P=0.001), but not in patients with LUSC (P=0.088). In conclusion, LINC00628 expression was upregulated in NSCLC and associated with patient prognosis. Patients with LUAD had higher LINC00628 expression levels than those with LUSC, and increased LINC00628 served as an independent prognostic factor in LUAD, but not LUSC.

Identification of Immune-Related Gene Signatures in Lung Adenocarcinoma and Lung Squamous Cell Carcinoma.

Accumulating evidence indicates that immunotherapy helped to improve the survival and quality-of-life of patients with lung adenocarcinoma (LUAD) or lung squamous cell carcinoma (LUSC) besides chemotherapy and gene targeting treatment. This study aimed to develop immune-related gene signatures in LUAD and LUSC subtypes, respectively. LUAD and LUSC samples were divided into high- and low-abundance groups of immune cell infiltration (Immunity_H and Immunity_L) based on the abundance of immune cell infiltrations. The distribution of immune cells was significantly different between the high- and low-immunity subtypes in LUAD and LUSC samples. The differentially expressed genes (DEGs) between those two groups in LUAD and LUSC contain some key immune-related genes, such as PDL1, PD1, CTLA-4, and HLA families. The DEGs were enriched in multiple immune-related pathways. Furthermore, the seven-immune-related-gene-signature (CD1B, CHRNA6, CLEC12B, CLEC17A, CLNK, INHA, and SLC14A2) prognostic model-based high- and low-risk groups were significantly associated with LUAD overall survival and clinical characteristics. The eight-immune-related-gene-signature (C4BPB, FCAMR, GRAPL, MAP1LC3C, MGC2889, TRIM55, UGT1A1, and VIPR2) prognostic model-based high- and low-risk groups were significantly associated with LUSC overall survival and clinical characteristics. The prognostic models were tested as good ones by receiver operating characteristic, principal component analysis, univariate and multivariate analysis, and nomogram. The verifications of these two immune-related-gene-signature prognostic models showed consistency in the train and test cohorts of LUAD and LUSC. In addition, patients with LUAD in the low-risk group responded better to immunotherapy than those in the high-risk group. This study revealed two reliable immune-related-gene-signature models that were significantly associated with prognosis and tumor microenvironment cell infiltration in LUAD and LUSC, respectively. Evaluation of the integrated characterization of multiple immune-related genes and pathways could help to predict the response to immunotherapy and monitor immunotherapy strategies.

In silico assessment of EpCAM transcriptional expression and determination of the prognostic biomarker for human lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC)

Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein which is involved in cell signaling, proliferation, maturation, and movement, all of which are crucial for the proper development of cells and tissues. Cleavage of the EpCAM protein leads to the up-regulation of c-myc, e-fabp, and cyclins A and E which promote tumorigenesis. EpCAM can act as potential diagnostic and prognostic biomarker for different types of cancers as it is also found to be expressed in epithelia and epithelial-derived neoplasms. Hence, we aimed to analyze the EpCAM gene expression and any associated feedback in the patients of two major types of lung cancer (LC) i.e., lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), based on the publicly available online databases. In this study, server-based gene expression analysis represents the up-regulation of EpCAM in both LUAD and LUSC subtypes as compared to the corresponding normal tissues. Besides, the histological sections revealed the over-expression of EpCAM protein in cancerous tissues by depicting strong staining signals. Furthermore, mutation analysis suggested missense as the predominant type of mutation both in LUAD and LUSC in the EpCAM gene. A significant correlation (P-value < 0.05) between the higher EpCAM expression and lower patient survival was also found in this study. Finally, the co-expressed genes were identified with their ontological features and signaling pathways associated in LC development. The overall study suggests EpCAM to be a significant biomarker for human LC prognosis.

Comprehensive Molecular Characterizations of Chinese Patients With Different Subtypes of Lung Squamous Cell Carcinoma.

BackgroundThis study aims to profile integrative genomic spectra of Chinese patients with different subtypes of lung squamous cell carcinoma (LUSC) and explore potential molecular prognosis factors.MethodsWe retrospectively identified 204 surgically resected LUSC patients in Shanghai Chest Hospital who underwent capture-based targeted next-generation sequencing (NGS) with a panel of 68 lung cancer‐related genes from September 2017 to January 2019. NGS was used to profile comprehensive molecular characterizations.ResultsOf 204 cases, 114 (55.9%) were keratinizing squamous cell carcinoma (KSCC), 77 (37.7%) were non-keratinizing squamous cell carcinoma (NKSCC), 13 (6.4%) were basaloid squamous cell carcinoma (BSCC), respectively. All subtypes presented similarly high proportions of mutations, including TP53, CDKN2A, and NOTCH1. A comparable prevalence of FGFR1 amplifications was identified between KSCC and NKSCC (11.4 versus 26.9%, p = 0.007). Compared with NKSCC, IGF1R amplifications were more frequent in BSCC (0 versus 15.4%, p = 0.019). We found cases with TP53 alterations had less EGFR alterations in KSCC (P = 0.013, OR = 0.158). Compared with TCGA cohorts, our Chinese cohorts exhibited statistic differences in both somatic mutations and signaling pathways. We found that STK 11 alterations and TOP2A alterations were significantly associated with higher risk of recurrence in patients with LUSC.ConclusionsSignificant differences exist among three subtypes of LUSC in molecular characterizations.

Comprehensive Molecular Characterizations of Chinese Patients with Different Subtypes of Lung Squamous Cell Carcinoma

Background: This study aims to profile integrative genomic spectra of Chinese patients with different subtypes of lung squamous cell carcinoma (LUSC) and explore potential molecular prognosis factors. Methods: We retrospectively identified 204 surgically resected LUSC patients in Shanghai Chest Hospital who underwent capture-based targeted next-generation sequencing (NGS）with a panel of 68 lung cancer‐related genes from September 2017 to January 2019. NGS was used to profile comprehensive molecular characterizations. Findings: Of 204 cases, 114 (55.9%) were KSCC, 77 (37.7%) were NKSCC, 13 (6.4%) were BSCC, respectively. All subtypes presented similarly high proportions of mutations, including TP53, CDKN2A and NOTCH1. A comparable prevalence of FGFR1 amplifications was identified between KSCC and NKSCC (11.4% versus 26.9%, p = 0.007). Compared with NKSCC, IGF1R amplifications were more frequent in BSCC (0% versus 15.4%, p = 0.019). We found cases with TP53 alterations had less EGFR alterations in KSCC (P = 0.013, OR = 0.158). Compared with TCGA cohorts, our Chinese cohorts exhibited statistic differences in both somatic mutations and signaling pathways. We found that STK 11 alterations and TOP2A alterations were significantly associated with higher risk of recurrence in patients with LUSC. Interpretation: Significant differences exist among three subtypes of LUSC in molecular characterizations. Funding Statement: This work was supported by grants from Shanghai Municipal Science and Technology Commission Research Project (16431903200). Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: This study has been approved by the institutional review board of Shanghai Chest Hospital.

Correlation of clinicopathologic features and lung squamous cell carcinoma subtypes according to the 2015 WHO classification

AimsThis study aimed to determine the relationship between clinicopathologic features and lung squamous cell carcinoma (LSCC) subtypes according to the 2015 WHO classification. MethodsWe identified 824 operable LSCC patients undergoing a complete surgical resection at Shanghai Chest Hospital between April 2015 and January 2017. Immunohistochemistry was used to investigate the clinicopathologic features. ResultsAmong them, the percentages of LSCC subtypes were 66.1% (545/824), 28.6% (236/824), and 5.2% (43/824) for keratinizing squamous cell carcinoma (KSCC), nonkeratinizing squamous cell carcinoma (NKSCC), and basaloid squamous cell carcinoma (BSCC), respectively. There were more males, more smokers, and more pneumonectomy surgeries in KSCC patients (p = 0.008, p = 0.000, p = 0.043). There were more N2 lymph node involvement and pathological stage III in NKSCC patients (p = 0.01, p = 0.03). BSCC did not demonstrate specificity to anything, but expressed adenocarcinoma markers more frequently. No significant difference existed between pathological subtypes and other clinicopathologic features, such as age, location type, visceral pleural involvement and lymphovascular invasion. The frequencies of EGFR sensitive mutations and ALK rearrangements were not significantly different among three subtypes. ConclusionSignificant relationships exist between some clinicopathologic features and LSCC subtypes.

PUB094 Correlation of Clinicopathologic Features and Lung Squamous Cell Carcinoma Subtypes According to the 2015 WHO Classification

This study aimed to determine the relationship between clinicopathologic features and lung squamous cell carcinoma subtypes according to the 2015 WHO classification. We identified 368 operable lung squamous cell carcinoma patients who had undergone a complete surgical resection at Shanghai Chest Hospital between April 2015 and March 2016. Among all patients, the percentages of lung squamous cell carcinoma subtypes were: 68.5% (252/368), 26.2% (97/368), and 5.1% (19/368) for keratinizing squamous cell carcinoma (KSCC), nonkeratinizing squamous cell carcinoma (NKSCC), and basaloid squamous cell carcinoma (BSCC), respectively. There were more smokers in patients with KSCC than in patients with other subtypes (p=0.004). There were no significant relationships between pathological subtypes and other clinicopathologic features, such as gender, age, location type, type of resection, stage, visceral pleural involvement, lymphovascular invasion, and lymph node involvement. The expressions of P40, CK5/6, TTF-1, Napsin A, and CK7 were also not significantly different in three subtypes. Our study revealed that there were no significant relationships between clinicopathologic features and lung squamous cell carcinoma subtypes.

Differentiated regulation of immune-response related genes between LUAD and LUSC subtypes of lung cancers.

Lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) are the two major subtypes of lung cancer, with LUSC exhibits faster progression rate than LUAD. To investigate the roles of immune-response related genes (IRGs) in lung cancer progression, we used LUAD and LUSC samples at different cancer progression stages, and identified that the expression profiles of IRGs could serve as a better classification marker for cancerous tissues of both LUAD and LUSC. We found that the expression changes of IRGs were different between LUAD and LUSC. Cell cycle promoting genes, including KIFs and proteasomes, showed faster up-regulation in LUSC, whereas immune response promoting genes, including MHC molecules and chemokines, were more rapidly repressed in LUSC. Comparative pathway analysis revealed that members of the Toll-like receptor and T cell receptor signaling pathways exhibited diverged expression changes between LUAD and LUSC, especially at the early cancer stages. Our results revealed the difference of LUAD and LUSC from the immune response point of view, and provided new clues for the differential treatment of LUAD and LUSC.

Enhanced MAPK signaling drives ETS1-mediated induction of miR-29b leading to downregulation of TET1 and changes in epigenetic modifications in a subset of lung SCC.

Non-small-cell lung cancer is the leading cause of cancer death worldwide and is comprised of several histological subtypes, the two most common being adenocarcinoma (AC) and squamous cell carcinoma (SCC). Targeted therapies have successfully improved response rates in patients with AC tumors. However, the majority of SCC tumors lack specific targetable mutations, making development of new treatment paradigms for this disease challenging. In the present study, we used iterative non-negative matrix factorization, an unbiased clustering method, on mRNA expression data from the cancer genome atlas (TCGA) and a panel of 24 SCC cell lines to classify three disease segments within SCC. Analysis of gene set enrichment and drug sensitivity identified an immune-evasion subtype that showed increased sensitivity to nuclear factor-κB and mitogen-activated protein kinase (MAPK) inhibition, a replication-stress associated subtype that showed increased sensitivity to ataxia telangiectasia inhibition, and a neuroendocrine-associated subtype that showed increased sensitivity to phosphoinositide 3-kinase and fibroblast growth factor receptor inhibition. Additionally, each of these subtypes exhibited a unique microRNA expression profile. Focusing on the immune-evasion subtype, bioinformatic analysis of microRNA promoters revealed enrichment for binding sites for the MAPK-driven ETS1 transcription factor. Indeed, we found that knockdown of ETS1 led to upregulation of eight microRNAs and downregulation of miR-29b in the immune-evasion subtype. Mechanistically, we found that miR-29b targets the DNA-demethylating enzyme, TET1, for downregulation resulting in decreased 5-hmC epigenetic modifications. Moreover, inhibition of MAPK signaling by gefitinib led to decreased ETS1 and miR-29b expression with a corresponding increase in TET1 expression and increase in 5-hmC. Collectively, our work identifies three subtypes of lung SCC that differ in drug sensitivity and shows a novel mechanism of miR-29b regulation by MAPK-driven ETS1 expression which leads to downstream changes in TET1-mediated epigenetic modifications.