STIL is a regulatory protein essential for centriole biogenesis, and its dysregulation has been implicated in various diseases, including malignancies. However, its role in non-small-cell lung carcinoma (NSCLC) remains unclear. In this study, we examined STIL expression and its potential association with chromosomal numerical abnormalities (CNAs) in NSCLC using The Cancer Genome Atlas (TCGA) dataset, immunohistochemical analysis, and in vitro experiments with NSCLC cell lines designed to overexpress STIL. TCGA data revealed upregulated STIL mRNA expression in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), the two major subtypes of NSCLC. Immunohistochemical analysis of cases from our hospital (LUAD, n = 268; LUSC, n = 98) revealed STIL protein overexpression. To elucidate the functional role of STIL, an inducible STIL-overexpressing H1299 NSCLC cell line was generated. Overexpression of STIL in these cells promoted centrosome amplification, leading to chromosomal instability. Finally, analysis of arm-level chromosomal copy number alterations from the TCGA dataset revealed that elevated STIL mRNA expression was associated with CNAs in both LUAD and LUSC. These findings suggest that STIL overexpression is associated with CNAs in NSCLC, likely through centrosome amplification, which is linked to chromosomal instability and might represent a potential therapeutic target for NSCLC treatment.
DNA Polymerase Theta (POLQ) is a DNA polymerase involved in error-prone translesion DNA synthesis (TLS) and error-prone repair of DNA double-strand breaks (DSBs). In the present study, we examined whether abnormal POLQ expression may be involved in the pathogenesis of lung adenocarcinoma (LAC). First, we found overexpression of POLQ at both the mRNA and protein levels in LAC, using data from the Cancer Genome Atlas (TCGA) database and by immunohistochemical analysis of our LAC series. POLQ overexpression was associated with an advanced pathologic stage and an increased total number of somatic mutations in LAC. When H1299 human lung cancer cell clones overexpressing POLQ were established and examined, the clones showed resistance to a DSB-inducing chemical in the clonogenic assay and an increased frequency of mutations in the supF forward mutation assay. Further analysis revealed that POLQ overexpression was also positively correlated with Polo Like Kinase 4 (PLK4) overexpression in LAC, and that PLK4 overexpression in the POLQ-overexpressing H1299 cells induced centrosome amplification. Finally, analysis of the TCGA data revealed that POLQ overexpression was associated with an increased somatic mutation load and PLK4 overexpression in diverse human cancers; on the other hand, overexpressions of nine TLS polymerases other than POLQ were associated with an increased somatic mutation load at a much lower frequency. Thus, POLQ overexpression is associated with advanced pathologic stage, increased somatic mutation load, and PLK4 overexpression, the last inducing centrosome amplification, in LAC, suggesting that POLQ overexpression is involved in the pathogenesis of LAC.
This patient, a 53-year-old male, has had back pain and an abnormal shadow was detected in the right lung field on December 1989. He was admitted to the hospital for the further examination. On the diagnosis of lung cancer with high serum CEA level operation was performed on February 1990. As a results of pathological examination, histological type was adenocarcinoma and pathological stage was pT3N0M0 stage IIIA. After operation the serum CEA level was decreased immediately but it was gradually increased once again. And then 14 months later right adrenal metastasis was detected by abdominal CT with high serum CEA level and resection was performed. Similarly a solitary lymph node metastasis located in abdomen was detected and resected with high serum CEA level 28 months after second operation. In this case detection and resection of the metastatic lesion was managed effectively by serum CEA level. The patient had a good operative course and is alive 76 months after first operation without any evidence or recurrence.
Recent progress in targeted therapy for lung cancer has revealed that accurate differential diagnosis between squamous cell carcinoma (SCC) and adenocarcinoma (ADC) of the lung is essential. To identify a novel immunohistochemical marker useful for differential diagnosis between the two subtypes of lung cancer, we first selected 24 SCC-specific genes and 6 ADC-specific genes using data (case number, 980) from the Cancer Genome Atlas (TCGA) database. Among the genes, we chose the CLCA2 gene, which is involved in chloride conductance and whose protein expression in lung cancer is yet to be characterized, and evaluated its protein expression status in 396 cases of primary lung cancer at Hamamatsu University Hospital. Immunohistochemical analysis revealed a significantly higher CLCA2 expression level in the SCCs than in the ADCs (P < 0.0001) and also a significantly higher frequency of CLCA2 protein expression in the SCCs (104/161, 64.6%) as compared with that in the ADCs (2/235, 0.9%) (P < 0.0001; sensitivity 64.6%, specificity 99.1%). The CLCA2 protein expression status was associated with the histological tumor grade in the SCCs. These results suggest that CLCA2 might be a novel excellent immunohistochemical marker for differentiating between primary SCC and primary ADC of the lung.
The human TDG gene encodes a DNA glycosylase protein, which is involved in base excision repair and the regulation of gene expression. Since nonsynonymous variations in two other DNA glycosylase genes, OGG1 and MUTYH, are associated with an increased cancer risk, deleterious nonsynonymous variations in the TDG gene might also be associated with diseases, including cancer. In the present study, to identify deleterious variations in TDG, nucleotide variations in the coding region of the TDG gene were investigated using single nucleotide polymorphism (SNP) databases, and detected nonsynonymous variants were analyzed in silico from the standpoint of relevant protein function and stability. A total of 43 nonsynonymous SNPs consisting of 37 missense variations, 3 nonsense variations, and 3 frameshift variations were found in the TDG gene. Six of the 37 missense variants were predicted to be damaging or deleterious by three different software programs (PolyPhen-2, SIFT, and PROVEAN), and 28 of them were predicted to be less stable using both the I-Mutant 2.0 and MUpro software. Additionally, 6 nonsense or frameshift variants were predicted to produce a truncated TDG protein with a completely or partially lost DNA glycosylase domain. These results suggested that a subset of nonsynonymous SNPs in the TDG gene is associated with a reduced level of protein functional activity or stability.
Human WDR62, which is localized in the cytoplasm including the centrosome, is known to be responsible for primary microcephaly; however, the role of WDR62 abnormality in cancers remains largely unknown. In this study, we aimed to reveal the pathological role of WDR62 abnormality in lung adenocarcinoma (LAC). We first examined the WDR62 mRNA expression level of LAC ( n = 64) using a QRT‐PCR analysis and found that WDR62 mRNA transcripts were significantly overexpressed in LAC ( P = 0.0432, Wilcoxon matched pairs test). An immunohistochemical analysis for LAC ( n = 237) showed that WDR62 proteins were also significantly overexpressed in LAC ( P < 0.0001, Mann‐Whitney U test). A Kaplan‐Meier analysis demonstrated that patients with LAC who exhibit WDR62 overexpression have a short overall survival ( P = 0.0378, log‐rank test), and a multivariate analysis revealed that WDR62 overexpression was an independent predictor of a poor survival outcome among LAC patients (hazard ratio, 2.032; 95% confidence interval, 1.071‐3.777; P = 0.0305). Next, we examined the functional effect of WDR62 overexpression on the lung cancer cell line H1299. WDR62‐overexpressing lung cancer cells exhibited an increase in cell growth. Moreover, the concurrent overexpression of WDR62 and TPX2, a WDR62‐interacting protein that is also overexpressed in LAC, induced centrosome amplification in the lung cells. Finally, we disclosed that the concurrent overexpression of WDR62 and TPX2 is common in diverse human cancers, using data from the Cancer Genome Atlas. These results suggested that WDR62 overexpression is associated with a poor prognosis in patients with LAC and leads to an increase in the malignant potential of lung cells.
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