To gain more insight into the role of chromosomal instability (CIN), the cytogenetic hallmark of most solid tumors, we performed fluorescence in situ hybridization (FISH) on interphase nuclei of cytological specimens enabling the correct detection of chromosome copies in intact tumor cells of 18 well (G1), moderately (G2), or poorly (G3) differentiated hepatocellular carcinomas (HCCs). A close correlation between the morphological dedifferentiation and increasing copy numbers and variation of FISH signals was seen for chromosomes 1 and 8, respectively (P ≤ 0.0002). Four HCC G1 had constant chromosome patterns for chromosomes 1 and/or 8 with a mean of signals per nucleus ≤5.08 and ≤3 different signal combinations, indicating a low level of CIN, as confirmed by FISH using probes for centromeres of chromosomes 3, 7, and 17. In contrast to this, five HCC G2–3 revealed ≥8.46 signals per nucleus and 23–41 different signal combinations, indicating high levels of CIN. In the remaining cases, signal counts from 5.96–8.46 and 7–15 combinations were seen. Here, nuclei with constant aberration patterns and low copy numbers occurred alongside nuclei with inconstant patterns and high copy numbers. It is evident that in these cases a transition from well to moderately differentiated HCC developed in parallel to an increase in CIN, possibly induced by a major dysregulation of mitotic control mechanisms. In conclusion, CIN may induce a stepwise increase of aneuploidy in HCC that is mirrored by the morphological dedifferentiation of tumor cells.

Induction of aneuploidy by increasing chromosomal instability during dedifferentiation of hepatocellular carcinoma

Background The genes related to the cell cycle progression could be considered the key factors in human cancers. However, the genes involved in cell cycle regulation in non-small cell lung cancer (NSCLC) have not yet been reported. Therefore, it is necessary to evaluate the genes related to the cell cycle in all types of cancers, especially NSCLC. Methods This study constituted the first pan-cancer landscape of cell cycle signaling. Cluster analysis based on cell cycle signaling was conducted to identify the potential molecular heterogeneity of NSCLC. Further, the discrepancies in the tumor immune microenvironment, metabolic remodeling, and cell death among the three clusters were investigated. Immunohistochemistry was performed to validate the protein levels of the ZWINT gene and examine its relationship with the clinical characteristics. Bioinformatics analyses and experimental validation of the ZWINT gene were also conducted. Results First, pan-cancer analysis provided an overview of cell cycle signaling and highlighted its crucial role in cancer. A majority of cell cycle regulators play risk roles in lung adenocarcinoma (LUAD); however, some cell cycle genes play protective roles in lung squamous cell carcinoma (LUSC). Cluster analysis revealed three potential subtypes for patients with NSCLC. LUAD patients with high cell cycle activities were associated with worse prognosis; while, LUSC patients with high cell cycle activities were associated with a longer survival time. Moreover, the above three subtypes of NSCLC exhibited distinct immune microenvironments, metabolic remodeling, and cell death pathways. ZWINT, a member of the cell signaling pathway, was observed to be significantly associated with the prognosis of LUAD patients. A series of experiments verified the higher expression levels of ZWINT in NSCLC compared to those in paracancerous tissues. The activation of epithelial-mesenchymal transition (EMT) induced by ZWINT might be responsible for tumor progression. Conclusion This study revealed the regulatory function of the cell cycle genes in NSCLC, and the molecular classification based on cell cycle-associated genes could evaluate the different prognoses of patients with NSCLC. ZWINT expression was found to be significantly upregulated in NSCLC tissues, which might promote tumor progression via activation of the EMT pathway.

https://www.frontiersin.org/articles/10.3389/fendo.2023.1147366/pdf

Identification of the cell cycle characteristics of non-small cell lung cancer and its relationship with tumor immune microenvironment, cell death pathways, and metabolic reprogramming

Background Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer (LC). However, the early-stage diagnostic rate is still low, and the 5-year overall survival (OS) rate remains poor. The present study aimed to identify critical genes as diagnostic and prognostic markers and small-molecule drugs for combating LUAD using a systematic bioinformatics analysis. Methods Five gene expression profiling datasets were systematically integrated and analyzed. First, gene coexpression modules were identified, and differentially expressed genes (DEGs) were screened. Second, the functional changes of these DEGs were systematically investigated. Third, the protein-protein interaction network, high correlation module and key genes were identified. Fourth, prognosis and diagnostic analyses were performed. Fifth, small-molecule drugs were predicted for guiding LUAD therapy. Results Finally, 12-gene and 2-gene signatures were identified as diagnostic and prognostic markers. The areas under the curves (AUCs) of two signatures associated with 3-year survival were 0.686 and 0.603, respectively. The AUCs of two signatures were over 95% and 94% in diagnostic model, separately. Eleven small-molecule drugs were found and irinotecan was simultaneously predicted in three drug databases. Conclusions The present study identified some key dysregulated genes involved in LUAD and potential drugs by a comprehensive analysis, which provides novel insights into the pathological mechanism involved in LUAD and may shed light on the diagnosis, prognosis and treatment of LUAD patients.

/pdf/systematically-integrative-analysis-identifies-diagnostic-54l5pwes1b.pdf

Systematically integrative analysis identifies diagnostic and prognostic candidates and small-molecule drugs for lung adenocarcinoma

Human Zwint-1 Specifies Localization of Zeste White 10 to Kinetochores and Is Essential for Mitotic Checkpoint Signaling

Background and aim: ZW10 interacting kinetochore protein 1 (Zwint-1), one of the major kinetochore proteins, is essential for kinetochore function, such as spindle assembly checkpoint function and kinetochore-microtubule attachment. Recently, it has been found over-expressed in some human cancers, including ovarian cancer, bladder cancer, and pulmonary adenocarcinoma. However, few studies of the expression of Zwint-1 in hepatocellular carcinoma (HCC) have been reported. This study is aimed to investigate the expression of Zwint-1 and its relationship with clinical pathological characters in HCC. Methods: The expression of Zwint-1 protein was analyzed by immunohistochemistry staining on tissue microarrays containing 171 HCC tissues and 187 control non-tumorous liver tissues. The relationships between the Zwint-1 expression and the clinicopathological parameters, and survival analysis were investigated using SPSS software 13.0. Results: Zwint-1 was found uniformly expressed in adjacent non-tumorous liver tissues (184/187, 98.40%), while was significantly decreased in HCC tissues, or even absent (150 of 171, 61.82%, P<0.001). The expression of Zwint-1 was negatively associated with age, tumor size, and Edmondson Grade. Besides, HCC patients with low Zwint-1 expression were also correlated with poor overall survival of the patients. Conclusions: Decreased expression of Zwint-1 was associated with poor prognosis in HCC.

Decreased expression of Zwint-1 is associated with poor prognosis in hepatocellular carcinoma.

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Decreased expression of Zwint-1 is associated with poor prognosis in hepatocellular carcinoma.