Introduction Cellular senescence is a hallmark of tumors and has potential for cancer therapy. Cellular senescence of tumor cells plays a role in tumor progression, and patient prognosis is related to the tumor microenvironment (TME). This study aimed to explore the predictive value of senescence-related genes in thyroid cancer (THCA) and their relationship with the TME. Methods Senescence-related genes were identified from the Molecular Signatures Database and used to conduct consensus clustering across TCGA-THCA. Differentially expressed genes (DEGs) were identified between the clusters used to perform multivariate Cox regression and least absolute shrinkage and selection operator regression (LASSO) analyses to construct a senescence-related signature. TCGA dataset was randomly divided into training and test datasets to verify the prognostic ability of the signature. Subsequently, the immune cell infiltration pattern, immunotherapy response, and drug sensitivity of the two subtypes were analyzed. Finally, the expression of signature genes was detected across TCGA-THCA and GSE33630 datasets, and further validated by RT-qPCR. Results Three senescence clusters were identified based on the expression of 432 senescence-related genes. Then, 23 prognostic DEGs were identified in TCGA dataset. The signature, composed of six genes, showed a significant relationship with survival, immune cell infiltration, clinical characteristics, immune checkpoints, immunotherapy response, and drug sensitivity. Low-risk THCA shows a better prognosis and higher immunotherapy response than high-risk THCA. A nomogram with perfect stability constructed using signature and clinical characteristics can predict the survival of each patient. The validation part demonstrated that ADAMTSL4, DOCK6, FAM111B, and SEMA6B were expressed at higher levels in the tumor tissue, whereas lower expression of MRPS10 and PSMB7 was observed. Discussion In conclusion, the senescence-related signature is a promising biomarker for predicting the outcome of THCA and has the potential to guide immunotherapy.

/pdf/identification-and-validation-of-a-novel-senescence-related-39cc4r28.pdf

Identification and validation of a novel senescence-related biomarker for thyroid cancer to predict the prognosis and immunotherapy

Objectives The short-term effects of microwave ablation (MWA) for the treatment of benign thyroid nodules (BTNs) were satisfactory in previous studies. However, as a slowly progressing disease, the long-term efficacy of MWA for BTNs at present is not clear. Our study aim was to assess the long-term results of MWA for BTNs after a 48-month follow-up. Methods From June 2015 to September 2017, 148 patients had 148 BTNs. All patients were from the China-Japan Union Hospital of Jilin University. Careful ultrasound examinations were performed 1 day, 1 month, 3 months, 6 months, 12 months, and every 6 months after MWA. The volume, volume reduction rate (VRR), recurrence rate of the ablated area and thyroid function were recorded. Results The mean volumes of the 148 nodules were 15.6 ± 9.4 cm3 (range: 1.3-48.9 cm3) and 0.6 ± 0.6 cm3 (range: 0-3.5 cm3) before and 48 months after MWA, respectively, with a nodule VRR of 96.9 ± 2.5% (range: 90.4-100%). Two patients (1.35%) had recurrence after MWA. Compared with thyroid function before MWA, no significant variation was observed after MWA. Five patients experienced complications (3.38%): two patients (1.35%) had bleeding, two patients (1.35%) had ear pain and toothache during MWA, and one patient (0.68%) had hoarseness after MWA. No cases of oesophageal injury, tracheal injury, infection, skin burns, etc., were reported during or after MWA. Conclusions Based on a long-term follow-up, MWA is an effective method for treating BTNs and is expected to be a potential first-line treatment.

/pdf/long-term-outcome-of-microwave-ablation-for-benign-thyroid-3uatrsm3.pdf

Long-term outcome of microwave ablation for benign thyroid nodules: Over 48-month follow-up study

Abstract Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal human malignancies, and with quite limited treatment alternatives. The proteasome is responsible for most of the protein degradation in eukaryotic cells and required for the maintenance of intracellular homeostasis. However, its potential role in HCC is largely unknown. In the current study, we identified eukaryotic translation initiation factor 3 subunit H (EIF3H), belonging to the JAB1/MPN/MOV34 (JAMM) superfamily, as a bona fide deubiquitylase of O- GlcNAc transferase (OGT) in HCC. We explored that EIF3H was positively associated with OGT in HCC and was related to the unfavorable prognosis. EIF3H could interact with, deubiquitylate, and stabilize OGT in a deubiquitylase-dependent manner. Specifically, EIF3H was associated with the GT domain of ERα via its JAB/MP domain, thus inhibiting the K48-linked ubiquitin chain on OGT. Besides, we demonstrated that the knockdown of EIF3H significantly reduced OGT protein expression, cell proliferation and invasion, and caused G1/S arrest of HCC. We also found that the deletion of EIF3H prompted ferroptosis in HCC cells. Finally, the effects of EIF3H depletion could be reversed by further OGT overexpression, implying that the OGT status is indispensable for EIF3H function in HCC carcinogenesis. In summary, our study described the oncogenic function of EIF3H and revealed an interesting post-translational mechanism between EIF3H, OGT, and ferroptosis in HCC. Targeting the EIF3H may be a promising approach in HCC. 

The deubiquitinase EIF3H promotes hepatocellular carcinoma progression by stabilizing OGT and inhibiting ferroptosis

Hepatocellular carcinoma (HCC) is associated with a high mortality rate, where resistance to immunotherapy and chemotherapy plays a crucial role. A newly identified form of cell death called disulfidptosis shows promise, but its biological mechanism in HCC remains uncertain. In this study, a prognostic model was developed for Disulfidptosis-related long non-coding RNAs (DRLs) from 370 HCC patients sourced from TCGA-LIHC, utilizing five key features: AC026356.1, AC073254.1, PXN-AS1 expression, AC026412.3, and AC099066.2. High-risk HCC patients had lower survival, CD4+ T cell infiltration, and elevated immune checkpoint gene expression. Furthermore, based on the features of DRLs, HCC was classified into three subtypes. Notably, patients belonging to different subtypes demonstrated varying overall survival rates, immune cell infiltration patterns, and sensitivity to immune therapy. Moreover, the novel DRL AC026412.3 (HR = 40.207) emerged as the most significant prognostic factor, exhibiting high expression across all HCC cells. Elevated expression of AC026412.3 promoted HCC cell proliferation and induced resistance to gefitinib. In conclusion, we have discovered five DRLs and constructed a prognostic risk model. Our findings validate the correlation between DRL-related prognostic models, tumor subtypes, and the HCC immune microenvironment along with its implications for immunotherapy. Moreover, further investigation into the molecular mechanisms of key biomarkers like AC026412.3 in the future will contribute significantly to advancing our comprehension of HCC's pathogenesis and drug resistance mechanisms. 

Disulfidptosis-related lncRNA signatures assess immune microenvironment and drug sensitivity in hepatocellular carcinoma.

Abstract Purpose: The expression and regulatory mechanism of NSUN6 in lung cancer are still unclear. Our study explored whether NSUN6 mediates progression of lung cancer by affecting NM23-H1 expression in an m5C-dependent manner. Methods: qRT-PCR, CCK-8, colony formation, transwell, and Western blot analysis were employed to probe the impact of NSUN6 on lung cancer cell proliferation, migration, and epithelial-mesenchymal transition (EMT). RMVar database was utilized to forecast the downstream genes of NSUN6. The mode of interaction between NSUN6 and NM23-H1 was determined by dot blot, luciferase assay, m5C RIP, and cell function assays. The effect of NSUN6 expression on tumor growth was verified in vivo. Results: Expression of NSUN6 was reduced in lung cancer cells, and over-expression of NSUN6 restricted the proliferation of lung cancer cells, migration, and EMT. NSUN6 regulated NM23-H1 expression by modifying the 3′-UTR of NM23-H1 mRNA through m5C and inhibited lung cancer cell proliferation, migration, and EMT. In vivo experiments also showed that over-expression of NSUN6 inhibited the occurrence of lung cancer. Conclusion: NSUN6 regulates NM23-H1 expression in an m5C-dependent manner to affect EMT in lung cancer. Thus, NSUN6 may be considered as a potential therapeutic target for lung cancer. Highlights of the Study Levels of NSUN6 are low in lung cancer and may play a role in promoting cancer. NM23-H1 was downregulated in lung cancer cells. Over-expression of NSUN6 inhibits lung cancer cell proliferation, migration, and EMT by regulating NM23-H1. NSUN6 regulated NM23-H1 expression by modifying its mRNA 3′-UTR through m5C.

NSUN6 Regulates NM23-H1 Expression in an m5C Manner to Affect Epithelial-Mesenchymal Transition in Lung Cancer

The deubiquitinating enzyme UCHL3 promotes anaplastic thyroid cancer progression and metastasis through Hippo signaling pathway

5‐Methylcytosine (m5C) methylation is a major epigenetic RNA modification and is closely related to tumorigenesis in various cancers. This study aimed to explore the prognostic value of m5C‐related lncRNAs in breast cancer.

Development of the expression and prognostic significance of m5C‐related LncRNAs in breast cancer

Breast cancer (BC) is the leading malignancy among women worldwide.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/cam4.4545

The initial expression alterations occurring to transcription factors during the formation of breast cancer: Evidence from bioinformatics

Breast cancer (BC) is the most common neoplastic and lethal malignancy in women. Although antiendocrine therapy is the main treatment for estrogen receptor alpha (ERα)-positive BC, the development of resistance is a major clinical complication. In this study, we aimed to explore the role of ubiquitin-specific peptidase 8 (USP8) in ERα signaling and identify potential targets for endocrine resistance. Public databases were used to analyze USP8 expression, prognosis, clinical characteristics, and immune cell infiltration. Immunohistochemistry and western blot assays were used to detect protein levels and ERα signaling. Quantitative reverse transcription-PCR was used to measure ERα target gene expression. The cell counting kit-8, wound-healing, clone formation, and Transwell assays were used to investigate the effects of USP8 depletion or inhibition on cell proliferation, migration, and invasion. An immunofluorescence assay was used for localizing USP8 and ERα, and a protein stability assay was performed for detecting the degradation of ERα protein. The cell cycle and apoptosis were assessed using flow cytometry. USP8 was highly expressed in the luminal subtype of BC and was associated with poor prognosis. The infiltration levels of many immune cells were positively correlated with USP8 expression. Depletion of USP8 dramatically decreased the ERα signaling activity and weakened the proliferation, migration, and invasion capabilities of BC cells. USP8 knockdown markedly induced apoptosis and cell cycle arrest (G0/G1). Colocalization analysis and protein stability assays indicated a probable mechanism by which USP8 regulates ERα. Our study demonstrates that USP8 might be crucial in BC development and may be considered a potential target for treating ER-positive BC malignancies in vitro.

/pdf/ubiquitin-specific-peptidase-8-modulates-cell-proliferation-1285me0j.pdf

Ubiquitin-Specific Peptidase 8 Modulates Cell Proliferation and Induces Cell Cycle Arrest and Apoptosis in Breast Cancer by Stabilizing Estrogen Receptor Alpha


 Background Ovarian cancer (OC) has the highest fatality rate amongst all gynecologic malignancies. Exploring new factors and pathways associated with development of ovarian cancer would help to identify new therapeutic targets. Long non-coding RNAs (lncRNAs) play indispensable roles in the process of the progression of OC. Methods Reverse transcription-quantitative PCR (RT-qPCR) was performed to verify the expression of RAD51B-AS1 in cell lines and patients’ tissues. Cellular proliferation, metastasis and apoptosis were detected using Cell Counting Kit-8(CCK-8), colony formation, Transwell and flow cytometry assays, respectively. Mouse xenograft models were established to detect tumorigenesis. RT-qPCR, western blotting and immunofluorescence experiments were conducted to explore the quantitative and positional relationship between RAD51B-AS1 and its host gene, RAD51B. Co-transfection rescue experiments were then performed to preliminarily explore its mechanism in vivo and in vitro. Results RAD51B-AS1 was significantly upregulated in a highly metastatic human OC cell line and in OC tissues. RAD51B-AS1 significantly increased the proliferation and metastasis of OC cells, whilst also enhancing resistance to anoikis. Biogenetics prediction analysis revealed that the only target gene of RAD51B-AS1 was RAD51B. Subsequent gene function experiments revealed that RAD51B exerted the same biological effects as RAD51B-AS1. Rescue experiments demonstrated that the malignant biological behaviors promoted by RAD51B-AS1 overexpressing were partially or completely reversed by RAD51B silencing in vitro and in vivo.Conclusion RAD51B-AS1 promoted the malignant biological behavior of OC, and the underlying mechanism of this action may be associated with the positive regulation of RAD51B expression. The present study revealed a potentially novel molecular mechanism underlying the development of OC. RAD51B-AS1 is expected to serve as a novel molecular biomarker for the diagnosis and prediction of a poor prognosis in OC, and as a potential therapeutic target for management of the disease.

/pdf/lncrna-rad51b-as1-promotes-the-malignant-biological-behavior-3vo3grb4.pdf

LncRNA RAD51B-AS1 promotes the malignant biological behavior of ovarian cancer via upregulation of RAD51B

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