CCND1 as a Predictive Biomarker of Neoadjuvant Chemotherapy in Patients with Locally Advanced Head and Neck Squamous Cell Carcinoma

BACKGROUND: Cyclin D1 (CCND1) has been associated with chemotherapy resistance and poor prognosis. In this study, we tested the hypothesis that CCND1 expression determines response and clinical outcomes in locally advanced head and neck squamous cell carcinoma (HNSCC) patients treated with neoadjuvant chemotherapy followed by surgery and radiotherapy. METHODOLOGY AND FINDINGS: 224 patients with HNSCC were treated with either cisplatin-based chemotherapy followed by surgery and radiotherapy (neoadjuvant group, n = 100) or surgery and radiotherapy (non-neoadjuvant group, n = 124). CCND1 expression was assessed by immunohistochemistry. CCND1 levels were analyzed with chemotherapy response, disease-free survival (DFS) and overall survival (OS). There was no significant difference between the neoadjuvant group and non-neoadjuvant group in DFS and OS (p = 0.929 and p = 0.760) when patients treated with the indiscriminate administration of cisplatin-based chemotherapy. However, in the neoadjuvant group, patients whose tumors showed a low CCND1 expression more likely respond to chemotherapy (p<0.001) and had a significantly better OS and DFS than those whose tumors showed a high CCND1 expression (73% vs 8%, p<0.001; 63% vs 6%, p<0.001). Importantly, patients with a low CCND1 expression in neoadjuvant group received more survival benefits than those in non-neoadjuvant group (p = 0.016), however patients with a high CCND1 expression and treated with neoadjuvant chemotherapy had a significantly poor OS compared to those treated with surgery and radiotherapy (p = 0.032). A multivariate survival analysis also showed CCND1 expression was an independent predictive factor (p<0.001). CONCLUSIONS: This study suggests that some but not all patients with HNSCC may benefit from neoadjuvant chemotherapy with cisplatin-based regimen and CCND1 expression may serve as a predictive biomarker in selecting patients undergo less than two cycles of neoadjuvant chemotherapy

Impact of primary molars with periapical disease on permanent successors: A retrospective radiographic study

Objective: To clarify the effects on the development, position and morphology of the permanent successors of primary molars affected by apical periodontitis (AP). Method: A total of 132 panoramic radiographs of children aged from 4 to 10 were screened out and a total of 159 mandibular second primary molars with chronic apical periodontitis（AP）(93 males and 66 females) were analyzed. The maturation values of permanent successors were interpreted and scored according to Nolla's method and compared with normal ones'. The proportion of abnormalities in the morphology and orientation of permanent successors were counted, and the differences between men and women was analyzed. The distribution of various abnormalities in different age groups was also analyzed. Result: There were significant differences in development of permanent successors in this study compared with the normal ones' in all age groups, among which the differences were statistically significant in males aged in 4,5,7 groups and females aged in 4,6 (P < 0.05). The proportions of permanent successors involved with dental follicle broken, malposition and malformation were 78.94%, 42.1%, 8.42% and 82.50%, 38.75%, 15.00%, respectively, with no gender difference. And the highest proportion of these three were all found in 9 years old age group. Conclusion: AP of primary teeth can lead to accelerated or delayed development of permanent successors to some extent, and may also lead to changes in their shape and direction

ARHGAP21 Is Involved in the Carcinogenic Mechanism of Cholangiocarcinoma: A Study Based on Bioinformatic Analyses and Experimental Validation

Background and Objectives: Rho GTPase-activating protein (RhoGAP) is a negative regulatory element of Rho GTPases and participates in tumorigenesis. Rho GTPase-activating protein 21 (ARHGAP21) is one of the RhoGAPs and its role in cholangiocarcinoma (CCA) has never been disclosed in any publications. Materials and Methods: The bioinformatics public datasets were utilized to investigate the expression patterns and mutations of ARHGAP21 as well as its prognostic significance in CCA. The biological functions of ARHGAP21 in CCA cells (RBE and Hccc9810 cell) were evaluated by scratch assay, cell counting kit-8 assay (CCK8) assay, and transwell migration assay. In addition, the underlying mechanism of ARHGAP21 involved in CCA was investigated by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and the most significant signaling pathway was identified through gene set enrichment analysis (GSEA) and the Western blot method. The ssGSEA algorithm was further used to explore the immune-related mechanism of ARHGAP21 in CCA. Results: The ARHGAP21 expression in CCA tissue was higher than it was in normal tissue, and missense mutation was the main alteration of ARHGAP21 in CCA. Moreover, the expression of ARHGAP21 had obvious differences in patients with different clinical characteristics and it had great prognostic significance. Based on cell experiments, we further observed that the proliferation ability and migration ability of the ARHGAP21-knockdown group was reduced in CCA cells. Several pathological signaling pathways correlated with proliferation and migration were determined by GO and KEGG analysis. Furthermore, the PI3K/Akt signaling pathway was the most significant one. GSEA analysis further verified that ARHGAP21 was highly enriched in PI3K/Akt signaling pathway, and the results of Western blot suggested that the phosphorylated PI3K and Akt were decreased in the ARHGAP21-knockdown group. The drug susceptibility of the PI3K/Akt signaling pathway targeted drugs were positively correlated with ARHGAP21 expression. Moreover, we also discovered that ARHGAP21 was correlated with neutrophil, pDC, and mast cell infiltration as well as immune-related genes in CCA. Conclusions: ARHGAP21 could promote the proliferation and migration of CCA cells by activating the PI3K/Akt signaling pathway, and ARHGAP21 may participate in the immune modulating function of the tumor microenvironment

Identification of Metabolism-Associated Biomarkers for Early and Precise Diagnosis of Oral Squamous Cell Carcinoma

The 5-year survival rate for oral squamous cell carcinoma (OSCC), one of the most common head and neck cancers, has not improved in the last 20 years. Poor prognosis of OSCC is the result of failure in early and precise diagnosis. Metabolic reprogramming, including the alteration of the uptake and utilisation of glucose, amino acids and lipids, is an important feature of OSCC and can be used to identify its biomarkers for early and precise diagnosis. In this review, we summarise how recent findings of rewired metabolic networks in OSCC have facilitated early and precise diagnosis of OSCC

Advanced progress of spatial metabolomics in head and neck cancer research

Head and neck cancer ranks as the sixth most prevalent malignancy, constituting 5 % of all cancer cases. Its inconspicuous onset often leads to advanced stage diagnoses, prompting the need for early detection to enhance patient prognosis. Currently, research into early diagnostic markers relies predominantly on genomics, proteomics, transcriptomics, and other methods, which, unfortunately, necessitate tumor tissue homogenization, resulting in the loss of temporal and spatial information. Emerging as a recent addition to the omics toolkit, spatial metabolomics stands out. This method conducts in situ mass spectrometry analyses on fresh tissue specimens while effectively preserving their spatiotemporal information. The utilization of spatial metabolomics in life science research offers distinct advantages. This article comprehensively reviews the progress of spatial metabolomics in head and neck cancer research, encompassing insights into cancer cell metabolic reprogramming. Various mass spectrometry imaging techniques, such as secondary ion mass spectrometry, stroma-assisted laser desorption/ionization, and desorption electrospray ionization, enable in situ metabolite analysis for head and neck cancer. Finally, significant emphasis is placed on the application of presently available techniques for early diagnosis, margin assessment, and prognosis of head and neck cancer

Intercellular adhesion molecule 2 as a novel prospective tumor suppressor induced by ERG promotes ubiquitination-mediated radixin degradation to inhibit gastric cancer tumorigenicity and metastasis

Abstract Background Gastric cancer (GC) is a fatal cancer with unclear pathogenesis. In this study, we explored the function and potential mechanisms of intercellular adhesion molecule 2 (ICAM2) in the development and advancement of GC. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were performed to quantify ICAM2 expression in harvested GC tissues and cultured cell lines. Immunohistochemical analyses were conducted on a GC tissue microarray to quantify ICAM2 expression and explore its implication on the prognosis of GC patients. In vitro experiments were carried out to reveal the biological functions of ICAM2 in GC cell lines. Further, in vivo experiments were conducted using xenograft models to assess the impact of ICAM2 on GC development and metastasis. Western blot, immunofluorescence, immunoprecipitation, luciferase assay, chromatin immunoprecipitation, and ubiquitination analysis were employed to investigate the underlying mechanisms. Results ICAM2 expression was downregulated in GC, positively correlating with advanced T stage, distant metastasis, advanced clinical stage, vessel invasion, and shorter patient survival time. ICAM2 overexpression suppressed the proliferation, migration, invasion, metastasis of GC cells as well as their ability to form tumors, whereas ICAM2 knockdown yielded opposite results. Erythroblast transformation-specific-related gene (ERG) as a transcription factor promoted the transcription of ICAM2 by binding to the crucial response element localized within its promoter region. Further analysis revealed that ICAM2 reduced radixin (RDX) protein stability and expression. In these cells, ICAM2 bound to the RDX protein to promote the ubiquitination and degradation of RDX via NEDD4 Like E3 Ubiquitin Protein Ligase (NEDD4L), and this post-translational modification resulted in the inhibition of GC. Conclusions In summary, this study demonstrates that ICAM2, which is induced by ERG, suppresses GC progression by enhancing the ubiquitination and degradation of RDX in a NEDD4L-dependent manner. Therefore, these results suggest that ICAM2 is a potential prognostic marker and a therapeutic target for GC

Additional file 3 of Intercellular adhesion molecule 2 as a novel prospective tumor suppressor induced by ERG promotes ubiquitination-mediated radixin degradation to inhibit gastric cancer tumorigenicity and metastasis

Additional file 3. Restoration of RDX reverses the antitumor effect of ICAM2 overexpression in GC. (a) The efficiency of RDX overexpression was confirmed by RT-PCR. (b) Representative image of the wound healing assays. (c) The apoptosis of ICAM2-overexpressing cells treated with RDX was confirmed by flow cytometry. (d) Transfection efficiency after overexpression of RDX in GC cells was determined by western blot

Additional file 2 of Intercellular adhesion molecule 2 as a novel prospective tumor suppressor induced by ERG promotes ubiquitination-mediated radixin degradation to inhibit gastric cancer tumorigenicity and metastasis

Additional file 2. The predicted E3 ubiquitin ligases of RDX. (a) UbiBrowser was used to predict the E3 ubiquitin ligases of the RDX. (b) RT-PCR was performed to verify the knockdown efficiency of the main E3 ubiquitin ligases in GC cells

Additional file 1 of Intercellular adhesion molecule 2 as a novel prospective tumor suppressor induced by ERG promotes ubiquitination-mediated radixin degradation to inhibit gastric cancer tumorigenicity and metastasis

Additional file 1. ICAM2 plays tumour‐suppressive roles in GC cell. (a) The efficiency ICAM2 overexpression or knockdown were confirmed by RT-PCR. (b) Flow cytometry analysis of the effect of ICAM2 overexpression or knockdown on the cell cycle progression of GC cells. (c) Flow cytometry results showing the effect of ICAM2 overexpression or knockdown on the apoptosis of GC cells. (d) Representative image of the wound healing assays