Disruptions in the circadian rhythm are linked to various diseases. The clock gene DEC1 is related to the progression and recurrence of various types of cancer; however, its role in colorectal cancer has not been determined. Therefore, we aimed to evaluate the significance of DEC1 expression level in colorectal cancer and its relationship with prognosis.

Nasopharyngeal carcinoma (NPC) is a virally associated epithelial malignancy with a high prevalence in East Asia. While Epstein-Barr virus (EBV) infection is a well-established risk factor, the role of host immune-related genetic variants remains insufficiently understood. Interleukin-12 (IL-12), a key immunoregulatory cytokine, is essential for EBV-specific T-cell responses, however, the impact of IL-12A gene polymorphisms on NPC susceptibility remains unknown.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths, often due to liver metastases. Neoantigen-based immunotherapy has shown promise in clinical trials of solid tumors, including CRC. However, the immunogenic factors of neoantigens and their optimal selection in metastatic tumors are not well understood. Therefore, this study aimed to identify the relationship between tumor mutation burden and immunogenicity of neoantigens in CRCs and metastatic CRCs and evaluate the changes in immunogenic neoantigens between the primary and metastatic lesions in metastatic CRCs.

Triple-negative breast cancer (TNBC) is an aggressive malignancy with few available targeted therapies. In this study, we examined the predictive power of several biomarkers, comprising the IMmunotherapy Against GastrIc Cancer (IMAGiC) model, PD-L1 combined positive score (CPS), intra-tumoral tumor-infiltrating lymphocytes (iTILs), and stromal TILs (sTILs), in an Asian population of patients with metastatic TNBC treated with immunotherapy.

To investigate the effects of acyclic retinoid (ACR) on v-raf murine sarcoma viral oncogene homolog BV600E (BRAFV600E)-mutant melanoma cells and its potential to overcome vemurafenib resistance by targeting the mitogen-activated protein kinase (MAPK)/phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase 1 (AKT)/mammalian target of rapamycin (mTOR) pathways.

The poor prognosis of triple-negative breast cancer (TNBC) is largely due to the lack of targeted therapies, as a result of the absence of estrogen, progesterone, and HER2 receptors. Our previous studies highlighted Del-1 as a potential therapeutic target and biomarker for TNBC. This study further explores molecules regulated by Del-1 through transcriptomic analysis.

Our study was designed to assess whether paired normal-tumour testing increased access to targeted therapy, clinical trials and influenced cancer screening recommendations given to patients and their families.

Chimeric antigen receptor T (CAR-T) cell therapy is under clinical investigation in patients with metastatic triple-negative breast cancer (TNBC). However, the identification of targetable antigens remains a high priority to avoid toxicity and prevent tumor escape.

Liquid biopsies using circulating tumour DNA (ctDNA) have emerged as an alternative to conventional biopsies. They can be used to aid in diagnosing and selecting an agent for treatment and can possibly be used to monitor disease response to treatment. In this report, we present a patient who initially presented with lower abdominal pain. Imaging showed extensive retroperitoneal lymphadenopathy and lymph node biopsy demonstrated poorly differentiated carcinoma. Further workup did not reveal a primary lesion, but his genetic analysis revealed a BRAF V600E mutation and CD274 amplification which was used to guide treatment of the adenocarcinoma as a melanoma of unknown primary. He was initiated on ipilimumab and nivolumab and his ctDNA levels showed rapid improvement. After treatment was stopped due to adverse events, he was monitored via ctDNA, with an increase prompting repeat imaging that demonstrated enlargement of his lesions prompting a resumption of treatment.

The long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (lncRNA MALAT1) and microRNA-145-5p (miR-145) axis play a pivotal role in regulating drug resistance, apoptosis and senescence in non-small cell lung cancer (NSCLC). MALAT1 drives drug resistance by suppressing miR-145 and activating MUC1, thereby inhibiting ferroptosis; however, its precise role in regulating ferroptosis in NSCLC remains unclear. Therefore, we propose a computational modelling approach to unravel the impact of the MALAT1/miR-145 axis on ferroptosis and drug resistance, to identify potential therapeutic strategies that promote ferroptosis. Using Boolean logic and a stochastic updating scheme, we developed and validated a robust regulatory model that encompasses ferroptosis, apoptosis, senescence and drug resistance pathways. The model, based on extensive literature and validated through gain- and loss-of-function perturbations, demonstrated strong alignment with observed clinical data that were not included in its construction. Our analysis identified three previously unreported feedback loops, miR-145/Wip1/p53, miR-145/Myc/MALAT1 and miR-145/MUC1/BMI1, establishing miR-145 as a central regulator in NSCLC. Perturbations targeting MALAT1 and wild-type p53-induced phosphatase 1 (Wip1) revealed potential therapeutic opportunities, with miR-145 activation emerging as a promising strategy to induce ferroptosis and overcome drug resistance. These findings highlight the MALAT1/miR-145 axis as a transformative therapeutic target, presenting a computational foundation to advance NSCLC treatment strategies.

NR2F6 is an orphan nuclear receptor with dual tumorigenic activity in the immune system and tumor cells, playing an essential role in tumor differentiation and immunity. This study aimed to investigate the expression level of NR2F6 in various tumors and its effect on neuroblastoma (NB).

Combined hepatocellular carcinoma-cholangiocarcinoma (HCC-CCA) is a rare liver tumor comprising histologic features of both HCC and CCA. Due to its heterogeneous nature, treatment of combined HCC-CCA is a significant clinical challenge and prognosis remains poor. Therefore, further understanding of the tumor biology underlying the individual subtypes of this mixed tumor is required to improve treatment stratification and optimize treatment strategies. This study sought to identify altered epigenetic regulation and gene expression patterns in the individual components of combined HCC-CCA. Formalin fixed paraffin embedded (FFPE) tumor specimens from 9 patients diagnosed with combined HCC-CCA were utilized in this study. Hematoxylin and eosin (H&E) staining was performed for each sample, and regions representative of the individual HCC and CCA components were delineated. Adjacent unstained slides were cut and dissected to separate HCC and CCA components. DNA and RNA extraction was performed for each sample for DNA methylation (n = 7 HCC and 7 CCA) and gene expression (n = 7 HCC and 8 CCA) profiling via reduced representation bisulfite sequencing (RRBS) and RNA-seq, respectively. Samples did not cluster by tumor type when comparing genome-wide DNA methylation or gene expression patterns. Of the 5 patients with DNA methylation data available for both subtypes, 4 clustered by patient as opposed to cancer subtype, suggesting similar epigenetic regulatory patterns arising from development in the same microenvironment and genetic background. Differential analysis resulted in the identification of 57 differentially expressed genes (DEGs) and 808 differentially methylated regions (DMRs) between the HCC and CCA subtypes. Genes associated with DMRs were associated with Wnt signaling, voltage-gated channels, metal binding, and cellular regulation. Finally, increased expression of several genes previously implicated in tumor aggressiveness, prognosis, and treatment responses were identified. These results highlight the potential importance of accounting for underlying HCC and CCA tumor biology when determining the optimal course of treatment for this deadly disease.

Delineating the mechanisms that control the movement of cells is central to understanding diverse physiological and pathophysiological processes. The transcriptional coactivator YAP is important during development and associated with cancer metastasis. Here, we found that YAP promoted cell migration by modulating a Rho family guanosine triphosphatase (GTPase) switch involving Rac1 and RhoA, which are key regulators of cytoskeletal dynamics. YAP transcriptionally transactivated the gene encoding the Rac1 guanine nucleotide exchange factor TRIO by directly binding to its intronic enhancer. This led to the activation of Rac1 and inhibition of RhoA, which increased cell migration and invasion in vitro and in vivo. This YAP-dependent program was observed across many cell types, including human breast epithelial cells and astrocytes, but it was particularly enhanced in a patient-specific manner in glioblastoma (GBM), the most common malignant brain tumor. Additionally, YAP-TRIO signaling activated STAT3, a transcription factor implicated in invasive growth in cancer, suggesting potential for cross-talk with this pathway to exacerbate invasive behavior. Clinically, hyperactivation of YAP, TRIO, and STAT3 gene signatures in GBM were associated with poor survival outcomes in patients. Our findings suggest that the YAP-TRIO-Rho-GTPase signaling network regulates invasive cell spread in both physiological and pathological contexts.

This study aims to evaluate the efficacy of chemotherapy and optimize treatment strategies for patients with advanced ovarian cancer.

This study aims to investigate metabolic reprogramming heterogeneity in hepatocellular carcinoma (HCC) cells and identify novel therapeutic targets for HCC treatment. Single-cell RNA sequencing data from public databases were used to analyze the TME of HCC and reveal the characteristics of different cell subsets, including mononuclear phagocytes, epithelial cells, endothelial cells, NK/T cells, B cells, and unknown cells. The analysis revealed that these cell subsets play their own unique roles in tumor progression and immune escape. Analysis of copy number variations (CNVs) was performed on tumor-derived epithelial cells, with the epithelial cells in Cluster 3 subgroup showing the highest CNV levels. Gene Ontology (GO) enrichment analysis revealed that these cell subsets were involved in a variety of biological processes such as immune response, cell communication, and metabolic pathways, which were consistent with their functional roles. Pseudotemporal analysis further delineated the malignant trajectory of HCC cells, with Cluster 3 exhibiting enhanced phosphatidylinositol metabolism, suggesting a critical role for metabolic reprogramming in tumor invasion and proliferation. Furthermore, a diagnostic model incorporating metabolic reprogramming-associated gene signatures was established, which effectively distinguished HCC from normal tissues. Among these signatures, splicing factor 3a subunit 3 (SF3A3) was identified as both diagnostic and independent prognostic biomarker. Mechanistically, SF3A3 knockdown in HCC cell lines significantly suppressed proliferation, migration, PI3K/AKT signaling, and EMT marker expression, thereby demonstrating its role in driving HCC aggressiveness. In conclusion, these findings elucidate novel molecular characteristics of HCC based on metabolic reprogramming, while establishing SF3A3 as a promising multi-faceted target for HCC diagnosis, prognostic assessment, and therapeutic intervention.

Melanocyte development involves key pathways that are often recapitulated during melanoma initiation, highlighting the importance of understanding these regulatory processes. Our study identifies mgat4b, a glycosyl transferase involved in selective N-glycan branching enriched in pigment progenitors, as a regulator of directional cell migration and establishment of melanocyte stem cell (McSC) pool during early development. Single cell RNA (scRNA) sequencing analysis in zebrafish upon targeted disruption of mgat4b reveals, that migratory melanocyte progenitors marked by galectin expression fail to persist. Lectin affinity proteomic analysis reveals the glycosylation of key melanocyte proteins GPNMB, KIT, and TYRP1 to be under the control of MGAT4B in melanocytic cells. Additionally, mislocalization of Junctional plakoglobin (JUP) explains the observed defects in cell adhesion and migration to be regulated by MGAT4B but not its isozyme MGAT4A. Our meta-analysis further reveals that melanoma patients with both the BRAFV600E mutation and elevated MGAT4B levels have significantly worse survival outcomes compared to those with only the BRAFV600E mutation. By leveraging the zebrafish MAZERATI platform to model BRAFV600E driver mutation in vivo, we show that mgat4b mutant cells fail to aggregate and initiate tumors. RNA profiling of the transformed melanocytes revealed cell-cell junction, adhesion, and ECM binding to be probable contributing factors that resulted in the failure of tumor onset. Using a small-molecule inhibitor we demonstrate that complex N-glycosylation inhibits early-stage melanoma progression. Our study underscores the importance of selective N-glycan branching in both melanocyte development and melanoma initiation, suggesting MGAT4B as a promising therapeutic target for melanoma treatment.

Noncanonical proteins, encoded by previously overlooked genomic regions (part of the "dark genome"), are emerging as crucial players in human health and disease, expanding our understanding of the "dark proteome." This review explores their landscape, including proteins derived from long non-coding RNAs, circular RNAs, and alternative open reading frames. Recent advances in ribosome profiling, mass spectrometry, and proteogenomics have unveiled their involvement in critical cellular processes. We examine their roles in cancer, neurological disorders, cardiovascular diseases, and infectious diseases, highlighting their potential as novel biomarkers and therapeutic targets. The review addresses challenges in identifying and characterizing these proteins, particularly recently evolved ones, and discusses implications for drug discovery, including cancer immunotherapy and neoantigen sources. By synthesizing recent findings, we underscore the significance of noncanonical proteins in expanding our understanding of the human genome and proteome, and their promise in developing innovative diagnostic tools and targeted therapies. This overview aims to stimulate further research into this unexplored biological space, potentially revolutionizing approaches to disease treatment and personalized medicine.

Chaperonin containing TCP1 subunit 5 (CCT5), a vital component of the molecular chaperonin complex, has been implicated in tumorigenesis, cancer stemness maintenance, and therapeutic resistance. Nevertheless, its comprehensive roles in pan-cancer progression, underlying biological functions, and potential as a predictor of immunotherapy response remains poorly understood.

Klotho, named after the youngest of the three Fates in Greek mythology daughters of Zeus and Nyx, who together spin the thread of life, allot destiny, and determine the time of passing for both mortals and immortals, is an important regulatory factor in aging and cancer dynamics. Initially described as an aging-suppressing protein, Klotho is now recognized for its more diverse role in modulating key signaling pathways like Wnt/β-catenin, IGF-1, PI3K/AKT, and TGF-β. Essentially, its various pro-cellular health functions, such as antioxidant, anti-inflammatory, and tumor-suppressive activities, are, in fact, considered that ensures the maintenance of cellular health and reduce complications related to aging. Klotho deficiency is associated with accelerated aging, chronic kidney disease, cardiovascular disorders, neurodegeneration, and various cancers. This review thus covers the twin roles of Klotho as an antiaging and tumor-suppressor protein, on their therapeutic potential, as well as advances in delivery systems and development of biomarkers and challenges for clinical translation.. Moreover, natural strategies like exercise and dietary interventions are explored that could help overcome Klotho deficiency. Further research with Klotho may offer a paradigm shift in the treatment of aging and cancer and add yet another avenue to increase survival of the patients.

Hepatocellular carcinoma (HCC) remains one of the most prevalent and lethal malignancies worldwide, with survival rates still falling short of expectations. Emerging evidence highlights the pivotal roles of both m6A methylation and ferroptosis-related genes (FRGs) in HCC progression. However, the prognostic significance of m6A-modulated FRGs remains largely unexplored. In this study, we developed a novel prognostic signature based on m6A-regulated FRGs, identifying six key genes (VEGFA, FANCD2, ZFP69B, EIF2S1, SLC7A11, and SRXN1) through multivariate and LASSO Cox regression analyses. A high m6A-FRGs score was strongly associated with poor prognosis, and multivariate analysis confirmed it as an independent prognostic factor. Notably, the high-risk group exhibited increased expression of immune checkpoint genes and a higher frequency of gene mutations. Functional assays further demonstrated that silencing ZFP69B significantly suppressed liver cancer cell proliferation, migration, and invasion. Clinical validation in 144 HCC samples revealed that elevated ZFP69B expression correlated with worse patient outcomes. Moreover, qPCR analysis confirmed CLSPN and HNRNPR as downstream targets of ZFP69B. Collectively, our findings establish the m6A-FRGs signature as a powerful prognostic tool for HCC and identify ZFP69B as a promising therapeutic target, warranting further investigation.