Laryngeal carcinoma is the predominant kind of tumor seen under the category of head and neck malignancies. LncRNA MIR600HG affects tumor morphology in numerous cancer types. However, the function of MIR600HG in laryngeal cancer remains unclear. Protein and gene expressions were analyzed by using western blot and quantitative real time polymerase chain reaction. Cells proliferation and migration were evaluated by EdU and transwell assays. Flow cytometry was performed to detect cells apoptosis. The interaction between MIR600HG or B-cell translocation gene 2 (BTG2) and miR-424-5p was analyzed by dual luciferase reporter assay and RNA immunoprecipitation. The expression of MIR600HG in laryngeal cancer tissues was lower than that in normal tissues, and low expression of MIR600HG was associated with poor prognosis in laryngeal cancer. Furthermore, overexpression of MIR600HG resulted in a reduction in cellular proliferation and the promotion of apoptosis in both HEp-2 and Tu-212. Mechanically, miR-424-5p was a direct target of MIR600HG, and overexpression of MIR600HG reduced miR-424-5p expression. Furthermore, BTG2 was a target gene of miR-424-5p and miR-424-5p upregulation suppressed the expression of BTG2. In addition, overexpression of BTG2 inhibited laryngeal cancer progression, whereas MIR600HG knockdown or miR-424-5p overexpression reversed the role of BTG2. This work suggested that MIR600HG represses laryngeal tumor development by regulating the miR-424-5p/BTG2 axis, which provides new molecules for early diagnosis of laryngeal cancer in the future.

Smoking-associated epigenetic changes have been linked to lung cancer (LC) risk; however, the role of epigenetic alterations independent of smoking is yet to be fully understood. This study aimed to validate 16 previously reported CpG sites that are independent of smoking yet associated with LC risk within a population-based prospective cohort. Using the Infinium Methylation EPIC BeadChip kit or the Infinium HumanMethylation450K BeadChip Assay, DNA methylation (DNAm) in whole blood was assessed in four subsets (n = 736, 1027, 997, and 312) of a population-based cohort from Germany. The DNAm levels of the 16 smoking-independent CpG sites were analyzed. Hazard ratios (HRs) and their 95% confidence intervals (95% CIs) were calculated to assess associations of DNAm at the 16 CpG sites with LC risk, adjusting for multiple covariates, including smoking habits and a smoking-associated DNAm score. Over 17 years of follow-up, a total of 199 LCs were observed. Among the 16 CpGs, cg02211449 showed a negative association with LC risk (HR [95% CI] per SD increase, = 0.70 [0.63-0.78]), while cg11385536 (1.04 [1.01-1.07]), cg09736286 (1.64 [1.10-2.44]), cg19907023 (1.64 [1.01-2.66]), and cg22032485 (1.52 [1.04-2.21]) displayed positive associations with LC risk. Five of the 16 suggested smoking-independent CpGs could be externally validated as predictors of LC risk. Further research should address their potential contribution to enhanced LC risk stratification.

Patients with colorectal cancer (CRC) following renal transplantation require long-term immunosuppressants to prevent graft rejection. However, the impact of these immunosuppressants on the tumor immune microenvironment and the roles of immune cells within it remain poorly understood. We conducted comprehensive single-cell RNA sequencing on tumor and normal tissues from four CRC patients post renal transplantation and compared these with published data from 23 non-transplant CRC patients. We set four groups for detailed comparative analysis based on the renal transplantation status and tissue origin: non-renal transplantation normal (nRT_Normal), non-renal transplantation tumor (nRT_Tumor), renal transplantation normal (RT_Normal), renal transplantation tumor (RT_Tumor). Our analysis revealed significant tumor immune microenvironment landscape alterations in the transplantation group. CD8effector T cells of RT_Tumor showed significantly diminished cytotoxicity and tumor neoantigen recognition (p < 0.0001), while CD4FOXP3 regulatory T cells of RT_Tumor displayed a higher inhibitory score (p < 0.05), indicating preserved immunomodulatory potential compared with non-transplant CRC. Notably, significantly increased CTLA4 expression in T cells of RT_Tumor was found and testified (p < 0.05). Our findings provide novel mechanistic insights for understanding the immune landscape in renal transplant recipients with CRC and pave the way for potential immunotherapeutic strategies that may improve survival and quality of life for this patient population.

Cancer immunotherapy is increasingly used in clinical practice, but its success rate is reduced by tumor escape from the immune system. This may be due to the genetic instability of tumor cells, which allows them to adapt to the immune response and leads to intratumoral immune heterogeneity. The study investigated spatial immune heterogeneity in the tumor microenvironment and its possible drivers in a mouse model of tumors induced by human papillomaviruses (HPV) following immunotherapy. Gene expression was determined by RNA sequencing and mutations by whole exome sequencing. A comparison of different tumor areas revealed heterogeneity in immune cell infiltration, gene expression, and mutation composition. While the mean numbers of mutations with every impact on gene expression or protein function were comparable in treated and control tumors, mutations with high or moderate impact were increased after immunotherapy. The genes mutated in treated tumors were significantly enriched in genes associated with ECM metabolism, degradation, and interactions, HPV infection and carcinogenesis, and immune processes such as antigen processing and presentation, Toll-like receptor signaling, and cytokine production. Gene expression analysis of DNA damage and repair factors revealed that immunotherapy upregulated Apobec1 and Apobec3 genes and downregulated genes related to homologous recombination and translesion synthesis. In conclusion, this study describes the intratumoral immune heterogeneity, that could lead to tumor immune escape, and suggests the potential mechanisms involved.

We investigated the effectiveness and safety of nelarabine (NEL)-combined chemotherapy for newly diagnosed adult T-cell acute lymphoblastic leukemia (T-ALL) patients. We conducted a phase II trial, T-ALL213-O, where adult T-ALL patients aged 25 to 64 were treated by a regimen based on that used in our previous study, ALL202-O. The main modifications from ALL202-O to T-ALL213-O were as follows: (1) NEL-combined chemotherapy, instead of consolidation (C)1, was used for non-complete remission (CR) patients after induction therapy (IND)1 as IND2; (2) NEL treatments were inserted into C3 and C5 on day 29. Twenty-four patients were analyzed. Ten patients did not receive NEL treatment due to therapy termination prior to C3. Three-year event-free survival (EFS) was 70%, with 52% as the lower limit of its 90% confidence interval, which exceeded the threshold of 25%; thus, the study treatment was considered effective. The CR rates by IND1, IND2, and both were 75%, 100%, and 88%, respectively. The 5-year EFS and 5-year overall survival rates were 66% and 70%, respectively, with median follow-ups of 7.7 and 7.8 years. The addition of NEL improved the CR rate but not survival, compared with T-ALL patients in ALL202-O. Severe neuropathy after NEL administration was observed at a high frequency. Seven (50%) of 14 patients treated with NEL showed grade 3 peripheral neuropathy and/or gait disturbance. The neurotoxicity was considered stronger than that previously reported. Combination therapy of NEL at this dose and intensive multidrug chemotherapy is associated with a high risk of severe neurotoxicity (JALSG T-ALL213-O, UMIN000010642).

Long noncoding RNAs (lncRNAs) play pivotal roles in the development of human malignancies, though their involvement in oral squamous cell carcinoma (OSCC) remains incompletely understood. Using The Cancer Genome Atlas (TCGA) dataset, we analyzed expression of 7840 lncRNAs in primary head and neck squamous cell carcinoma (HNSCC) and found that upregulation of LINC02154 is associated with a poorer prognosis. LINC02154 knockdown in OSCC cell lines induced cell cycle arrest and apoptosis, and significantly attenuated tumor growth in vitro and in vivo. Notably, depletion of LINC02154 downregulated FOXM1, a master regulator of cell cycle-related genes. RNA pulldown and mass spectrometry analyses identified a series of proteins that could potentially interact with LINC02154, including HNRNPK and LRPPRC. HNRNPK stabilizes FOXM1 expression by interacting with the 3'-UTR of FOXM1 mRNA, which suggests LINC02154 and HNRNPK promote cell cycling by regulating FOXM1 expression. Additionally, LINC02154 positively regulates HNRNPK expression by inhibiting microRNAs targeting HNRPNK. Moreover, LINC02154 affects mitochondrial function by interacting with LRPPRC. Depletion of LINC02154 suppressed expression of mitochondrial genes, including MTCO1 and MTCO2, and inhibited mitochondrial respiratory function in OSCC cells. These results suggest that LINC02154 exerts its oncogenic effects by modulating the cell cycle and oxidative phosphorylation in OSCC, highlighting LINC02154 as a potential therapeutic target.

Integrins are transmembrane receptors that facilitate cell adhesion to the extracellular matrix and neighboring cells. Aberrant expression of integrins has been associated with tumor progression and metastasis in various cancer types. Integrin alpha-5 (ITGA5) is an integrin subtype that serves as a receptor for fibronectin, fibrinogen, and fibrillin-1. The purpose of this study was to elucidate how ITGA5 expression plays a role in human non-small cell lung cancer (NSCLC). Our clinical data, along with data retrieved from The Cancer Genome Database (TCGA), revealed that high ITGA5 expression in NSCLC patients was associated with a lower recurrence-free survival and overall survival. In our in vitro functional assays, ITGA5 overexpression in human NSCLC cell lines resulted in increased cell size, adhesion, and migration properties, while knockdown of ITGA5 restored the phenotypes. Correspondingly, knockdown and inhibition of ITGA5 in endogenously high-expressing NSCLC cell lines resulted in decreased cell size, adhesion, migration, and proliferation. The antiproliferative effect was also confirmed by a reduction in Ki-67 without discernible changes in apoptosis. Collectively, these findings reveal the significant role of ITGA5 in various functional behaviors in NSCLC, providing a potential therapeutic target for NSCLC patients with high ITGA5 expression.

Metastasis is a major cause of cancer-related deaths. Similar to the tumor microenvironment formation, the premetastatic niche develops in distant organs before the arrival of tumor cells. Elucidating the mechanism(s) underlying premetastatic niche formation could contribute to the establishment of effective therapeutic targets for metastasis. Our research indicates that primary tumors hijack Toll-like receptor 4 (TLR4) signaling to establish a premetastatic niche in the lungs by utilizing an endogenous ligand S100A8. S100A8 is expressed not only in immune cells but also in various types of tumor cells. By focusing on S100A8 as a therapeutic target, we identified at least three multivalent S100A8 inhibitory peptides. Here, we review the tumor-promoting role of S100A8-mediated TLR4 signaling and propose S100A8 as a potential therapeutic target for aggressive cancer.

The expectations for artificial intelligence (AI) technology have increased considerably in recent years, mainly due to the emergence of deep learning. At present, AI technology is being used for various purposes and has brought about change in society. In particular, the rapid development of generative AI technology, exemplified by ChatGPT, has amplified the societal impact of AI. The medical field is no exception, with a wide range of AI technologies being introduced for basic and applied research. Further, AI-equipped software as a medical device (AI-SaMD) is also being approved by regulatory bodies. Combined with the advent of big data, data-driven research utilizing AI is actively pursued. Nevertheless, while AI technology has great potential, it also presents many challenges that require careful consideration. In this review, we introduce the current status of AI-based cancer research, especially from the perspective of clinical application, and discuss the associated challenges and future directions, with the aim of helping to promote cancer research that utilizes effective AI technology.

Genome-wide association studies (GWAS) statistically assess the association between tens of millions of genetic variants in the whole genome and a phenotype of interest. Genome-wide association studies enable the elucidation of polygenic inheritance of cancer, in which myriad low-penetrance genetic variants collectively contribute to a substantial proportion of the heritable susceptibility. In addition to the robust genotype-phenotype associations provided by GWAS, combining GWAS data with functional genomic datasets or sophisticated statistical genetic methods unlocks deeper insights. Integrating genotype and molecular phenotyping data facilitates functional characterization of GWAS association signals through molecular quantitative trait loci mapping and transcriptome-wide association studies. Furthermore, aggregating genome-wide polygenic signals, including subthreshold associations, enables one to estimate genetic correlations across diverse phenotypes and helps in clinical risk predictions by evaluating polygenic risk scores. In this review, we begin by summarizing the rationale for GWAS of cancer, introduce recent methodological updates in the GWAS-derived downstream analyses, and demonstrate their applications to GWAS of cancers.

Most cancer cells show increased chromosome missegregation, known as chromosomal instability (CIN), which promotes cancer progression and drug resistance. The underlying causes of CIN in cancer cells are not fully understood. Here we found that breast cancer cell lines show a reduced kinetochore localization of ROD, ZW10, and Zwilch, components of the fibrous corona, compared with non-transformed breast epithelial cell lines. The fibrous corona is a structure formed on kinetochores before their end-on attachment to microtubules and plays a role in efficient kinetochore capture and the spindle assembly checkpoint. The reduction in the fibrous corona was not due to reduced expression levels of the fibrous corona components or to a reduction in outer kinetochore components. Kinetochore localization of Bub1 and CENP-E, which play a role in the recruitment of the fibrous corona to kinetochores, was reduced in cancer cell lines, presumably due to reduced activity of Mps1, which is required for their recruitment to kinetochores through phosphorylating KNL1. Increasing kinetochore localization of Bub1 and CENP-E in cancer cells restored the level of the fibrous corona. Cancer cell lines showed a reduced capacity to nucleate microtubules from kinetochores, which was recently shown to be dependent on the fibrous corona, and increasing kinetochore localization of Bub1 and CENP-E restored the microtubule nucleation capacity on kinetochores. Our study revealed a distinct feature of cancer cell lines that may be related to CIN.

Breast cancer is a heterogeneous disease and is one of the most prevalent cancers in women. Triple-negative breast cancer (TNBC) is a relatively aggressive subtype of breast cancer, which is difficult to treat. Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type I transmembrane protein that is overexpressed in various types of cancers, including breast cancer, especially TNBC. In this study, bioinformatic analyses revealed enhanced fibroblast growth factor receptor 1 (FGFR1) signaling in patients with invasive breast cancer, and the GPNMB/FGFR1 group exhibited a lower probability of relapse-free survival (RFS) than the GPNMB/FGFR1 group. Additionally, we observed that GPNMB and FGFR1 were essential for sphere formation, cellular migration, and epithelial-mesenchymal transition (EMT)-like changes in TNBC cells. To explore the mutual interaction between these two molecules, we conducted in silico protein-protein docking studies and molecular dynamics simulations. The results revealed that GPNMB isoform b exhibits high binding affinity for FGFR1 isoform c (FGFR1c), which correlates with cancer aggressiveness. We also confirmed the interaction between GPNMB and FGFR1 in TNBC cells. Furthermore, our study demonstrated that GPNMB is essential for AKT phosphorylation at T308 following FGF2 stimulation, resulting in high affinity for FGFR1c. Inhibition of AKT phosphorylation substantially reduces the tumorigenic potential of TNBC cells.

Projections of future gastric cancer incidence and the demand for health-care services for gastric cancer patients by geographic area will assist local authorities in determining health-care needs, allocating medical resources, and planning services. This study aims to project the future incidence of gastric cancer, estimate the number of patients per medical institution, and decompose the net changes in cases to assess the impact of population aging by geographic area. Our projections are based on population-based cancer registry data, census data from 2000 to 2020, and the projected population for 2025-2045 in Kanagawa, Japan. We classified Kanagawa into urban, town, outer city, and rural areas based on geographic and population features. The number of medical institutions providing gastric cancer treatment was used to estimate the number of patients per medical institution. We projected a decrease of 25%, 52%, and 5% in gastric cancer cases in towns, outer cities, and rural areas from 2020 to 2045, respectively. However, cases are expected to increase by 9% in urban areas, primarily due to population aging. The annual number of gastric cancer patients per medical institution in urban areas is expected to increase from 54 to 59, while numbers in other areas are predicted to decline from 2020 to 2045. Our long-term projections indicate that the number of older gastric cancer patients will continue to increase in urban areas. While current measures effectively reduce gastric cancer risk, they need to be revised to address the impact of population aging.

Cancer stem cells aggregate to form clusters, which have enhanced stem-like properties and metastasis potential. However, the molecular mechanisms underlying the formation of cancer stem cell cluster-like structures with acquisition of stronger invasion and metastasis abilities remain unclear. Micropapillary carcinoma (MPC) is a subpopulation of small, merulioid, inverted, nonfibrous vascular clusters floating in the stroma present in a range of solid malignant tumors and characterized by frequent vascular/lymphatic vessel invasion and lymph node metastasis. Our results showed that these cell clusters exhibit a stem cell phenotype, supporting the premise that MPC may serve as a promising solid tumor model for studying invasion and metastasis of cancer stem cell clusters. In this review, we discuss the latest advances in MPC research and targeted therapy, focusing on analysis of their stem-like characteristics, mapping their multiomics characteristics, and elucidating the vascular and immune microenvironment of MPC. The existing MPC organoid model was employed to explore potential breakthroughs in targeted therapy and immunotherapy for cancer stem cell clusters.

Adipose tissue and bacterial flora are involved in metabolism in the human body. However, the relationship between the two remains unclear. Recently, the presence of circulating bacterial DNAs has been reported. We previously reported the utility of bacterial DNA in serum extracellular vesicles (EVs) for diagnosing patients with renal cell carcinoma (RCC). In this study, we aimed to assess whether there is a correlation between bacterial DNA in serum EVs and inflammation in adipose tissue. We undertook 16S rRNA metagenomic analysis of bacterial DNA in serum EVs from 77 patients with RCC (the derivation cohort). We discovered that DNAs from Enterobacteriaceae, Polaromonas, and Coxiellaceae were highly expressed in patients with low Mayo adhesive probability (MAP) scores. A lower MAP score reflects a reduced risk of dense adipose tissue and adhesions. Additionally, we combined these bacterial DNAs to create the EPC (Enterobacteriaceae, Polaromonas, Coxiellaceae) index that predicts a MAP score of 0. Subsequently, we undertook 16S rRNA metagenomic analysis of bacterial DNA in serum EVs from 32 patients with RCC (the validation cohort). The EPC index could distinguish patients with low MAP scores from those with high MAP scores in the derivation (area under the curve [AUC], 0.76; sensitivity, 56%; specificity, 85%) and validation (AUC, 0.81; sensitivity, 100%; specificity, 62%) cohorts. These results suggest that bacterial DNA in serum EVs could reflect the inflammation of adherent perinephric fat around the kidney.

The pan-immune-inflammation value reflects the systemic inflammatory response, and tumor-infiltrating lymphocytes indicate a local immune response in rectal cancer. However, the association between systemic inflammatory response, as indicated by the pan-immune-inflammation value, and local immune responses in rectal cancer remains unclear. This study analyzed 915 treatment-naïve rectal cancer patients from the Peking Union Medical College Hospital and PLA General Hospital (PLAGH) cohorts who underwent radical surgery to investigate the relationship between the pan-immune-inflammation value and immune responses. Lower pan-immune-inflammation value was significantly associated with improved disease-free survival and cancer-specific survival. Multivariate Cox regression models identified the pan-immune-inflammation value as an independent prognostic factor. In the PLAGH cohort, patients with low pan-immune-inflammation values had higher immune cell levels, activated immune pathways, and increased expression of immune checkpoint genes according to RNA sequencing. Hematoxylin and eosin staining and immunohistochemical analysis revealed that lower pan-immune-inflammation value was associated with higher tumor-infiltrating lymphocyte density, more mature tertiary lymphoid structures, increased CD8 T cells, and elevated human lymphocyte antigen class I expression. Conversely, patients with high pan-immune-inflammation values exhibited pathways linked to tumor progression, such as angiogenesis, epithelial-mesenchymal transition, hypoxia, KRAS signaling, and TGF-ß signaling. Among patients receiving anti-PD-1 therapy, responders had low pre- and post-treatment pan-immune-inflammation values. The pan-immune-inflammation value is a reliable marker associated with distinct immune microenvironment characteristics and can effectively predict disease-free survival, cancer-specific survival, and response to immunotherapy.

Human T-cell leukemia virus type 1 (HTLV-1) broadly impacts host genes, affecting the infected cell population and inducing the development of a disease with a poor prognosis, adult T-cell leukemia-lymphoma (ATL). This study aimed to provide a comprehensive epigenomic characterization of the infected cell population and evaluated the transcriptome and chromatin structures of peripheral blood cells in HTLV-1-infected individuals using RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin sequencing (ATAC-seq). The infected cells showed significant changes in gene expression patterns from the polyclonal stage and before ATL onset while demonstrating similarities to tumor-forming ATL cells. These similarities were a result of large-scale open chromatin changes, supporting the independent early formation of epigenomic aberrations as an underlying mechanism for later clonal propagation. This study also demonstrated that HTLV-1 Tax directly affects the host chromatin structure, thereby developing fundamental epigenomic characteristics. Several Tax target genes, including the RASGRP3-ERK pathway, were recognized, indicating an impact on signaling pathways. This genome-wide variability in chromatin structural property is a novel feature of HTLV-1 infection and may contribute to pathogenic mechanisms. In addition, it has crucial implications for better understanding the impact of HTLV-1 on the host genome and identifying novel therapeutic targets.

Malignant melanoma is characterized by high immunogenicity, genetic heterogeneity, and diverse pathological manifestations, affecting both skin and mucosa over the body. Pembrolizumab and nivolumab, both anti-PD-1 monoclonal antibodies, were approved by the US FDA for unresectable or metastatic melanoma in 2011 and 2014, respectively, with enduring and transformative outcomes. Despite marked clinical achievements, only a subset of patients manifested a complete response. Approximately 55% of melanoma patients exhibited primary resistance to PD-1 antibodies, with nearly 25% developing secondary resistance within 2 years of treatment. Thus, there is a critical need to comprehensively elucidate the mechanisms underlying the efficacy and resistance to PD-1 blockade. This review discusses the fundamental mechanisms of PD-1 blockade, encompassing insights from T cells and B cells, and presents resistance to anti-PD-1 with a particular focus on tumoral-intrinsic mechanisms in melanoma.

Multiple myeloma (MM) cells and osteoclasts (OCs) activate with each other to cause drug resistance. Human Th1-like Vγ9Vδ2 (γδ) T cells, important effectors against tumors, can be expanded and activated ex vivo by the aminobisphosphonate zoledronic acid in combination with IL-2. We previously reported that the expanded γδ T cells effectively targeted and killed OCs as well as MM cells. Because the expanded γδ T cells expressed CD16 on their surface, we investigated the utilization of the expanded γδ T cells for antibody-dependent cellular cytotoxicity (ADCC). Although the expanded γδ T cells alone induced cell death in MM cell lines, the addition of the anti-SLAMF7 monoclonal antibody elotuzumab (ELO) further enhanced their cytotoxic activity only against SLAMF7-expressing MM cell lines and primary MM cells. Intriguingly, ELO was also able to enhance γδ T cell-induced cell death against OCs cultured alone, and against both MM cells and OCs in their coculture settings. SLAMF7 was found to be highly expressed in OCs differentiated in vitro from monocytes by receptor activator of nuclear factor-κ B ligand and M-CSF, although monocytes only marginally expressed SLAMF7. These results demonstrate that SLAMF7 is highly expressed in both MM cells and OCs, and that the ex vivo-expanded γδ T cells can exert ELO-mediated ADCC against SLAMF7-expressing MM cells and OCs besides their direct cytotoxic activity. Further study is warranted for the innovative utilization of γδ T cells.

Hypopharyngeal and laryngeal cancers which belong to head and neck squamous cell carcinoma (HNSCC) are the two most malignant types of head and neck cancer, characterized by a low 5-year survival rate, high recurrence and metastasis rate. It is vital to explore strategies to suppress metastasis and improve prognosis for patients with these cancers. In this research, we analyzed the clinical data and found that E3 ubiquitin ligase TRIM47 was upregulated in cancer tissues of hypopharyngeal cancer and was closely associated with poor survival outcomes. In terms of mechanism, we performed tandem affinity chromatography and denatured Ni-NTA Agarose pulldown. As a result, TRIM47 was found to interact with vimentin and control vimentin stabilization through ubiquitination, specifically in the form of K63 chains. Importantly, through experiments of cancer cell viability and migration, we found that TRIM47 could enhance the proliferation and metastasis abilities of cancer cells in a vimentin-dependent manner, thus promoting the advancement of hypopharyngeal and laryngeal cancers. TRIM47 was verified to regulate cancer cells metastasis in vivo using metastasis models. All these results imply that TRIM47 emerges as a potential biomarker for early diagnosis and metastasis prediction of hypopharyngeal and laryngeal cancers and represents a promising therapeutic target.