The immune microenvironment contributes substantially to the biological and clinical heterogeneity of multiple myeloma (MM), yet immune-related molecular biomarkers with reproducible prognostic value remain limited. Here, we developed a 12-gene immune-related gene signature (IRGS) using an integrative machine-learning framework and evaluated its prognostic performance across multiple MM cohorts. The IRGS consistently stratified overall survival and remained independently associated with outcome after adjustment for established clinical covariates. Its prognostic discrimination was comparable to that of IFM15 and generally exceeded that of MRCIX6 and a mitophagy-related signature across the evaluated validation datasets. Single-cell RNA sequencing further revealed marked cell type-dependent variation in the activity of the 12-gene module, with comparatively low activity in plasma cells and higher activity in several non-plasma compartments, indicating that the bulk-derived IRGS reflects a multicellular bone marrow transcriptional context rather than an exclusively malignant plasma cell intrinsic program. Somatic mutation analysis identified distinct mutational patterns between IRGS-defined groups, including relative enrichment of DIS3 mutations in the low-IRGS group and MUC16 mutations in the high-IRGS group, together with a modestly higher tumor mutational burden in low-IRGS patients. Transcriptome-based drug-response prediction further suggested differential therapeutic vulnerabilities, with high- and low-IRGS groups showing distinct predicted sensitivity patterns across apoptosis-, DNA damage-, BET-, checkpoint-, and replication-stress-related agents. Collectively, these findings define the IRGS as a complementary immune-associated molecular biomarker for prognostic stratification in MM and provide a framework linking prognosis with multicellular transcriptional context, somatic mutational characteristics, and candidate therapeutic vulnerabilities.
Photodynamic therapy (PDT) is a localized treatment for esophageal stenosis and dysphagia in advanced cancer. This study evaluated the efficacy and safety of Cosiporfin sodium (DVDMS)-mediated PDT for dysphagia in advanced esophageal cancer. In this Phase II trial, patients with advanced esophageal cancer and Grade ≥ 2 dysphagia, who were unsuitable for or declined curative therapies, received 0.2 mg/kg DVDMS followed by PDT (wavelength: 630 nm) at varying regimens: 102 J/cm (24 h post-injection), 200 J/cm (24 h), and 150 J/cm (18 h). Safety was the primary endpoint. The study enrolled 20 patients in the 102 J/cm 24 h group, 6 in the 200 J/cm 24 h group, and 4 in the 150 J/cm 18 h group. Two patients experienced dose-limiting toxicities: One upper abdominal pain (16.7%) in the 200 J/cm 24 h group and one non-cardiac chest pain (25.0%) in the 150 J/cm 18 h group. Common adverse events included non-cardiac chest pain (10.0%) related to DVDMS and non-cardiac chest pain (20.0%) and anemia (20.0%) related to PDT. The photosensitivity test showed that by day 4, 66.7% of patients tested negative, improving to 86.7% by day 7, and all patients were negative by day 28. The esophageal overall response rate was 40.0% on day 28. The median duration of esophageal response and median OS for all patients were 4.86 months (95% CI: 1.51-5.32) and 9.51 months (95% CI: 5.45-NE), respectively. DVDMS-mediated PDT demonstrates acceptable safety and sustained efficacy in improving esophageal stenosis and dysphagia in advanced esophageal cancer. Trial Registration: chictr.org.cn ChiCTR2000032829.
This study aimed to develop and validate machine learning (ML) models integrating clinical parameters and the 2PI system (Pathology and Prognosis-Informed Imaging System) for predicting postoperative recurrence risk in hepatocellular carcinoma (HCC). The multicenter retrospective study included 496 patients with solitary HCC (≤ 5 cm). Surgical resection (SR) patients from the primary center constituted the training set; radiofrequency ablation (RFA) patients from the same center formed the internal test set; and SR patients from other centers served as the external test set. In the training set, multivariable logistic regression identified seven imaging features associated with pathological markers, with odds ratios calculated as exp(β). Kendall's tau-b coefficient was used to indicate the strength of association between pathology and recurrence risk. A dual-information pathway 2PI system was constructed based on these coefficients, and the performance of ML models integrating clinical parameters and the 2PI system was evaluated. A total of 496 patients (mean age 58 ± 10 years, 376 men) were enrolled. Patients were stratified into high- and low-risk groups using a 2PI system threshold of ≥ 19. The Random Survival Forest (RSF) model incorporating clinical parameters and the 2PI system demonstrated favorable predictive performance across all sets (training: C-index 0.76 [95% CI: 0.72-0.80]; internal test: C-index 0.69 [95% CI: 0.63-0.75]; external test: C-index 0.68 [95% CI: 0.57-0.79]). The 2PI system applies a joint weighting strategy to create a straightforward image scoring system that enhances postoperative recurrence risk prediction for solitary HCC, demonstrating preliminary generalizability across both SR and RFA cohorts.
Clear cell renal cell carcinoma (ccRCC) represents one of the most prevalent malignancies worldwide, characterized by high incidence and mortality rates. It is characterized by mitochondrial dysfunction with enhanced Warburg effect. In this study, we identify the sortilin-related receptor 1 (SORL1) as a regulator of ccRCC progression and a potential molecular target for oxidative phosphorylation inhibition. The present evidence demonstrates that SORL1 promotes the ubiquitin-mediated degradation of C-MYC via TRIM22, which is associated with the downregulation of ACO2 and IDH2 and a consequent suppression of oxidative phosphorylation capacity. Molecular investigations further indicated that Cefoperazone could bind to SORL1 and increase its protein level, exerting the SORL1-triggering function. Targeting delivery Cefoperazone exhibits unexpected anti-tumor performances in ccRCC. Collectively, our findings establish SORL1 as a tumor suppressor in ccRCC and highlight its potential as a therapeutic target in advancing ccRCC clinical treatment strategies.
Head and neck squamous cell carcinoma (HNSCC) is frequently managed with radiotherapy, but the emergence of radioresistant cancer cells with cancer stem cell (CSC) properties remains a major clinical obstacle. Here, we established a radioresistant FaDu cell line (F-IRR) by repeated fractionated irradiation to investigate the molecular basis of radiation resistance in HNSCC. Irradiated colony-forming assays confirmed the radioresistant phenotype of F-IRR cells. Although F-IRR cells proliferated more slowly than parental cells, they exhibited markedly enhanced CSC activity, as demonstrated by sphere formation, limiting dilution, and soft agar assays. Among multiple stem cell-associated markers, Musashi-1 (MSI1)-an ribonucleic acid (RNA)-binding protein with established roles in CSC maintenance-was the most prominently upregulated, as confirmed by western blot, reverse transcription-polymerase chain reaction (RT-PCR), and immunocytochemistry. Functional studies demonstrated that siRNA-mediated knockdown of MSI1 suppressed stemness and radioresistance in F-IRR cells, whereas stable MSI1 overexpression in parental FaDu and CAL27 cells conferred enhanced stemness and radiation resistance. RNA sequencing and pathway analysis identified hyperactivation of the mitogen-activated protein kinase (MAPK) pathway in F-IRR cells, and targeted inhibition experiments showed that the c-Jun N-terminal kinase (JNK) signaling pathway was the primary upstream regulator of MSI1 expression. JNK inhibition with SP600125 reduced MSI1 levels and attenuated stemness and radioresistance in F-IRR cells. In vivo xenograft experiments further confirmed that F-IRR cells possessed greater tumorigenic potential and radioresistance than parental cells, with high expression of MSI1 and phospho-JNK in tumor tissues. Collectively, these findings identify the JNK-MSI1 axis as a critical driver of CSC-mediated radioresistance in HNSCC and a promising therapeutic target for overcoming treatment failure.
Pancreatic ductal adenocarcinoma (PDAC) frequently harbors co-occurring alterations in KRAS, TP53, CDKN2A, and SMAD4, yet how clinically prevalent driver combinations shape kinase dependencies remains incompletely understood. To systematically interrogate genotype-dependent and shared vulnerabilities, we generated Drosophila models representing dominant PDAC driver contexts, including 2-hit (KRAS-TP53) and 3-hit (KRAS-TP53-CDKN2A or KRAS-TP53-SMAD4) genotypes, and conducted comparative whole-animal genetic screening using organismal viability as a phenotypic readout. This approach identified both genotype-specific modifiers and a subset of kinases whose suppression consistently improved viability across distinct genetic contexts, enabling prioritization of conserved candidates for cross-species validation. Among these, the Drosophila kinase Drak, orthologous to human STK17A/STK17B, emerged as a recurrent shared vulnerability. Functional validation in three-dimensional spheroid cultures of human PDAC cell lines representing distinct driver genotypes demonstrated that STK17B perturbation impairs spheroid growth across models. Transcriptomic profiling further revealed coordinated downregulation of gene sets linked to DNA replication and E2F-driven cell-cycle programs upon STK17B knockdown. Together, these findings establish a genotype-informed screening framework for systematic discovery of shared and context-dependent kinase dependencies in PDAC, and nominate STK17B as a conserved genetic vulnerability across dominant driver contexts.
Near-infrared photoimmunotherapy (NIR-PIT) is a new type of cancer treatment that specifically kills target cells while sparing normal tissue. This treatment induces cancer cell death by activating a photoreactive dye with near-infrared light in an antibody-photoabsorber conjugate (APC) bound to the cognate target antigen on the tumor cell surface. NIR-PIT has already been clinically applied in Japan to head and neck cancer patients using an anti-EGFR antibody-IR700 dye conjugate, with very promising results. Furthermore, preclinical studies have shown favorable results across many targets and cancer types. To date, APC administration in NIR-PIT has been performed via intravenous injection. However, some systemic administrations cause side effects. Therefore, local intratumoral injections might be a viable alternative in some cases. Thus, this study aimed to investigate the therapeutic effects of NIR-PIT following intratumoral administration of APC (IT-PIT) compared with NIR-PIT following intravenous administration of APC (IV-PIT) in various animal models and targets. Intratumoral administration of APC resulted in significantly greater distribution in the target tumor and less in non-tumor organs, showing that the APC can be efficiently delivered to tumor cells by intratumoral administration. In immunodeficient mice, IT-PIT showed similar efficacy to IV-PIT, despite a reduced dose of APC. In immunocompetent mice, IT-PIT showed a significant effect and extended survival, demonstrating the activation of antitumor immunity, comparable to that of IV-PIT. These results indicate that IT-PIT and IV-PIT are similarly effective in both direct cell killing and in inducing anticancer immune activation, suggesting that intratumoral administration of APC might be a promising new approach in NIR-PIT.
Tripartite motif-containing 59 (TRIM59) is an E3 ubiquitin ligase implicated in multiple malignancies, but its role in bladder cancer (BLCA) remains incompletely understood. In this study, we identified TRIM59 as a clinically relevant oncogenic driver in BLCA through integrated transcriptomic, clinical, and functional analyses. TRIM59 was significantly upregulated in BLCA tissues and cell lines, and high TRIM59 expression was associated with advanced stage, higher grade, recurrence, and poor prognosis. Functionally, TRIM59 promoted BLCA proliferation, cell-cycle progression, migration, invasion, and metastatic colonization in vitro and in vivo. Mechanistically, TRIM59 directly interacted with PTRF/Cavin-1 and induced its RING domain-dependent K48-linked polyubiquitination and proteasomal degradation. Additional mutagenesis analyses identified K98, K122, K152, and K317 as major ubiquitination sites on PTRF. In contrast to the oncogenic role of TRIM59, PTRF was downregulated in BLCA and exhibited tumor-suppressive properties. PTRF restoration attenuated TRIM59-driven proliferation, invasion, and epithelial-mesenchymal transition, whereas PTRF depletion partially rescued the inhibitory effects of TRIM59 silencing. Further analyses showed that PTRF restrains AKT phosphorylation and suppresses MYC transcriptional activity, thereby limiting c-Myc-driven proliferative signaling. Collectively, these findings define a previously unrecognized TRIM59-PTRF-AKT/c-Myc axis that drives BLCA progression and highlight TRIM59 as a potential prognostic biomarker and therapeutic target.
Tumor-infiltrating lymphocytes (TIL) therapy has demonstrated clinical potential in malignancies. However, limited understanding of why only a subset of patients respond to TIL therapy, coupled with the lack of simple and efficient methods to genetically engineer fragile TIL, has hindered efforts to enhance TIL efficacy through genetic modification. A T-Editor platform enabling rapid and efficient CRISPR-mediated gene editing in TIL was developed and optimized. To minimize the risk of chromosomal translocations associated with Cas9-induced double-strand breaks (DSBs), single-guide RNAs (sgRNAs) were designed for cytosine base editing (CBE). The expansion capacity, phenotypic profile, cytokine production, and in vitro cytolytic activity of base-edited TIL were compared with those of Cas9-KO TIL. In vivo efficacy was assessed using patient-derived xenograft (PDX) mouse models. The T-Editor platform was optimized for TIL gene editing by refining stimulation conditions, electroporation parameters, and CRISPR/Cas9 reagent dosing. FAM84B emerged as the top candidate, with its knockout resulting in the most pronounced enhancement of TIL cytolytic activity. CBE-mediated C·G-to-T·A conversion in the FAM84B exon achieved high editing efficiency with minimal insertion-deletion (indel) events. Base-edited TIL exhibited comparable expansion, phenotype, cytokine production, and in vitro cytolytic activity relative to Cas9-KO TIL. Compared with non-engineered control TIL, FAM84B-edited TIL displayed an increased CD62L+ memory subset, enhanced effector function and cytolytic activity, and improved in vivo antitumor efficacy. In conclusion, the T-Editor platform enables rapid and efficient CRISPR-mediated gene editing for engineering TIL to enhance its therapeutic potency. FAM84B may represent a novel potential target for improving TIL-mediated antitumor activity.
Cancer frequently develops in association with genomic instability, which includes massive induction of chromosomal structural variants (SVs) and single nucleotide variants (SNVs). SVs are typically caused by erroneous repair of DNA double-strand breaks (DSBs) and are tightly linked to cancer risk. Indeed, cancers often arise under DNA repair-deficient backgrounds such as BRCA1/2 mutations. However, many cancers exhibiting genomic instability occur without detectable defects in canonical repair pathways. The major exogenous risk factors include ionizing radiation (IR) and ultraviolet (UV) light, both of which induce multiple types of DNA damage. Long-standing questions are which specific types of DNA lesions induced by the irradiation contribute to genomic instability and how these lesions promote mutagenesis in cancer-driver genes. In this review, we summarize current knowledge regarding how IR and UV irradiation lead to genomic instability associated with mutation induction in cancer-driver genes.
Lung cancer remains the leading cause of cancer-related mortality worldwide, largely due to therapeutic resistance and tumor progression. Mitochondrial ribosomal proteins (MRPs), particularly MRPS23, have recently emerged as critical regulators of cancer progression in various malignancies, while N6-methyladenosine (m6A) modification has been established as a key epigenetic mechanism driving tumorigenesis. However, whether MRPS23 is regulated by m6A modification and contributes to lung cancer pathogenesis remains completely unexplored. Here, we identified MRPS23 as a critical oncogenic driver in non-small cell lung cancer (NSCLC). MRPS23 expression was significantly upregulated in NSCLC tissues and cell lines, and high MRPS23 levels correlated with poor patient prognosis. Mechanistically, we demonstrated that WTAP-mediated m6A methylation and subsequent IGF2BP3 recognition stabilized MRPS23 mRNA. Functionally, MRPS23 promoted lung cancer progression both in vitro and in vivo. Further mechanistic studies revealed that MRPS23 exerted its oncogenic effects through physical interaction with the molecular chaperone HSPA8, and this interaction was functionally associated with activation of the RAS-RAF-MEK-ERK signaling cascade. However, the precise molecular steps linking the MRPS23-HSPA8 complex to ERK phosphorylation remain to be fully defined. Collectively, our findings unveil a previously unrecognized m6A-dependent MRPS23/HSPA8/ERK regulatory axis in NSCLC progression, highlighting MRPS23 and its associated components as promising prognostic biomarkers and therapeutic targets.
HER2-mutant non-small cell lung cancer (NSCLC) comprises molecularly heterogeneous tumors with diverse ERBB2 mutation subtypes, and HER2-directed therapies have increased the need for refined molecular stratification. However, subtype-specific co-occurring genomic alterations remain incompletely characterized. We performed a two-stage clinicogenomic analysis to identify and validate recurrent co-mutations in HER2-mutant NSCLC. A public MSK-IMPACT lung adenocarcinoma cohort was used for discovery, and a nationwide Japanese real-world cohort from the Center for Cancer Genomics and Advanced Therapeutics was used for validation. In the MSK-IMPACT cohort of 2201 lung adenocarcinomas, TERT mutations were significantly enriched in ERBB2-mutant tumors compared with ERBB2-wild-type tumors (odds ratio, 2.40; 95% confidence interval, 1.12-4.70; p = 0.017). This association was reproduced in the independent validation cohort, where 16 of 174 HER2-mutant NSCLC cases harbored concurrent TERT mutations, all of which were promoter-region variants. Among the evaluated clinicogenomic variables, the ERBB2 mutation subtype was the only factor significantly associated with TERT mutation status. The ERBB2 G776-altered subtype remained independently associated with TERT mutation after multivariable adjustment (adjusted odds ratio, 7.49; 95% confidence interval, 1.81-31.0; p = 0.006). In a small exploratory subset of trastuzumab deruxtecan-treated patients (n = 52; TERT-mutated, n = 5), no statistically robust differences in treatment outcomes were observed according to TERT mutation status. TERT promoter mutations are recurrent co-mutations in HER2-mutant NSCLC and are preferentially associated with the ERBB2 G776-altered subgroup. These findings support ERBB2 subtype-aware molecular stratification and highlight previously underappreciated genomic heterogeneity within HER2-mutant NSCLC.
EGFR-mutant non-small cell lung cancer patients often exhibit resistance to TKI therapy. This treatment resistance is a key factor affecting the efficacy of TKIs and a major bottleneck in cancer treatment. The potential underlying cause may be closely related to tumor cell metabolic reprogramming. In this study, we established an EGFR-mutant lung cancer mouse model, isolating and culturing tumor primary cells to explore the cellular and molecular mechanisms of EGFR-mutant lung cancer. Using techniques such as super-resolution microscopy and RNA-seq, we qualitatively and quantitatively analyzed the morphological changes of mitochondria within tumor cells following TKI treatment. Our results indicate that mitochondrial dynamics are remodeled toward increased mitochondrial fission during the early phase of TKI treatment. Furthermore, pharmacological inhibition of mitochondrial fission further sensitizes tumor cells to EGFR-TKIs. Additionally, disrupting oxidative phosphorylation metabolism can increase the sensitivity of tumor cells to TKI treatment and reverse tumor cell resistance to TKI. Overall, these findings suggest that the metabolic reprogramming of mitochondrial OXPHOS in tumor cells mediates energy stress adaptation, altering their response to TKI treatment and providing new metabolic therapeutic targets to overcome EGFR-TKI resistance.
This Letter requests clarification of two data presentation issues in Onuki et al. (Cancer Science 2020): a numerical discrepancy in Table 2 and the unspecified age range in Figure 3 that may explain the 1000-case difference with Figure 4.
Quizartinib is a FMS-like tyrosine kinase 3 (FLT3) inhibitor indicated for FLT3 internal tandem duplication (FLT3-ITD)-positive acute myeloid leukemia (AML). We aimed to evaluate quizartinib resistance mechanisms, in addition to efficacy and safety outcomes, in patients with relapsed or refractory FLT3-ITD-positive AML. This multicenter, single-arm study in Japan (jRCTs071200015) enrolled 18 patients between May 2020 and December 2022. Of these, 15 patients received oral quizartinib (up to 53 mg once daily) for up to 12 cycles of 28 days each, then were followed for 12 months. The primary endpoint was to evaluate the type and rate of quizartinib resistance mutations; secondary endpoints included composite complete remission (CRc) rate, overall response rate (ORR), hematopoietic stem cell transplantation (HSCT) rate, relapse-free survival (RFS), overall survival (OS), and adverse events (AEs). Among seven evaluable patients, acquired mutations were detected in four patients (NF1 [R2616X], CSF3R [Q754X], NRAS [G13R], and FLT3 [D835Y] in one patient each), while loss of FLT3-ITD was observed in two patients. In efficacy analyses (n = 15), CRc rate was 66.7% (95% confidence interval [CI], 38.4-88.2), ORR was 73.3% (44.9-92.2), and median OS was 13.6 months (5.4-not evaluable). Three patients (20.0%) received HSCT directly after quizartinib; in these patients, median RFS was 8.5 months (95% CI, 6.2-not evaluable). Grade ≥ 3 non-hematologic AEs and grade 1 QT prolongation were each reported in three patients (20.0%). These data offer additional information on potential resistance mechanisms in patients with relapsed or refractory FLT3-ITD-positive AML. Trial Registration: Japan Registry of Clinical Trials (jRCTs071200015).
Cancer cells preferentially rely on aerobic glycolysis, known as the Warburg effect, to support growth and survival. We previously demonstrated that polypyrimidine tract-binding protein 1 (PTBP1) maintains PKM2 dominance by regulating pyruvate kinase isoform splicing, sustaining the Warburg phenotype. PTBP1 suppression shifts metabolism toward PKM1 dominance, enhancing oxidative phosphorylation, reactive oxygen species (ROS) production, apoptosis, and antitumor immunity. Thirteen chemically modified siR-PTBP1 derivatives targeting either the coding region or the 3'-untranslated region (3'-UTR) of PTBP1 mRNA were synthesized and evaluated in colorectal cancer cell lines. Cytotoxicity, protein expression, oxidative stress, and metabolic alterations were assessed using cell-based assays, immunoblotting, and metabolomic analysis. siRNA stability was evaluated following nuclease exposure and quantified by TaqMan RT-qPCR. siRNAs targeting the 3'-UTR more effectively suppressed PTBP1 expression and increased the PKM1/PKM2 ratio than coding-region-targeting siRNAs. Among them, derivative 2-6 showed the strongest cytotoxicity with oxidative stress and apoptosis. Metabolomic profiling demonstrated altered glycolytic flux and preserved pentose phosphate pathway intermediates with activated redox responses, while adenylate and guanylate energy charges remained viable, indicating metabolic stress without energy collapse. Tricarboxylic acid cycle metabolites were elevated, consistent with enhanced oxidative phosphorylation. Derivative 2-6 showed resistance to nuclease-mediated degradation. Direct PKM2 knockdown did not induce comparable cytotoxicity. Chemically modified siR-PTBP1, particularly derivative 2-6, induces a metabolically vulnerable state characterized by oxidative imbalance, leading to apoptosis. These findings identify PTBP1 as a key regulator of the Warburg effect and support siRNA-based metabolic targeting as a therapeutic strategy.
Tumor-associated macrophages (TAMs) and the complement system play pivotal roles in reshaping the chronic inflammatory microenvironment and driving malignant transformation. Although C1QA+ TAMs have been identified in multiple tumor types, their role in gastric cancer (GC) remains unexplored. Single-cell RNA sequencing (scRNA-seq) was performed on paired tumor tissues and adjacent tissues from three treatment-naïve patients to map macrophage heterogeneities. To evaluate the clinical and translational value of C1q, immunohistochemistry (IHC) was conducted on 100 GC samples, and C1q concentrations were measured via ELISA in plasma from a multi-center cohort of 240 patients and 100 GC tissue. Additionally, the effects of C1q-mediated THP-1-derived macrophages on the malignant behaviors of GC cells were investigated using in vitro migration. Transcriptomic analysis of 56,151 single cells successfully identified a distinct pro-inflammatory subset: C1QA+ TAMs. IHC staining demonstrated that C1q and CD163 were highly co-expressed in compromised tissues, and their elevated expression significantly correlated with poor patient prognosis. Multi-center plasma analysis revealed that elevated circulating C1q levels robustly enhanced clinical diagnostic accuracy. In vitro functional assays confirmed that C1q significantly primed M2 macrophage polarization, thereby accelerating the migration of GC cells. We first identified and functionally validated the C1QA+ TAM subset as a key driver of microenvironmental remodeling. C1q serves as a crucial mediator of macrophage polarization and holds strong promise as a novel, non-invasive biomarker for the early diagnosis.
Cholangiocarcinoma (CCA) constitutes a highly malignant tumor type demonstrating rising global incidence rates. Circular RNAs (circRNAs), characterized by their covalently bonded single-stranded loop configuration, have been identified as functional regulators across various cancer types. Previous studies have suggested circHECTD1's involvement in tumor processes, but its specific contributions and molecular pathways in CCA progression, particularly regarding autophagy regulation, remain unclear. Experimental data demonstrated significant upregulation of circHECTD1 in CCA cell lines, along with notable stability against RNase-mediated breakdown. From a functional perspective, increased circHECTD1 expression stimulated tumor cell growth, motility, invasive capacity, and autophagy processes, while triggering autophagosome formation. Mechanistically, circHECTD1 served as a molecular platform for the splicing factor SFPQ (proline- and glutamine-rich), facilitating SFPQ's binding to the ATG12 promoter regulatory region and enhancing the expression of ATG12 mRNA, resulting in increased transcriptional activity and enhanced mRNA durability, which in turn stimulated the autophagic process. When SFPQ was experimentally downregulated, this effect was diminished. Conversely, when autophagy was pharmacologically inhibited, the oncogenic effects mediated by circHECTD1 were effectively counteracted. These observations suggest that circHECTD1 plays a crucial role in the progression of CCA by forming a complex with SFPQ, which subsequently enhances both the transcription of ATG12 and the stability of ATG12 mRNA, thereby promoting autophagy and tumor progression.
Although multigene testing for advanced non-small cell lung cancer (NSCLC) is reimbursed in Japan, optimizing its real-world clinical impact remains challenging. This study updates nationwide testing trends and evaluates the treatment gap between diagnostic results and first-line therapeutic interventions. We conducted a retrospective cohort study using the Diagnosis Procedure Combination database (April 2019 to May 2024). The analysis included 24,047 patients with Stage IV NSCLC across 300 hospitals who underwent diagnostic lung biopsies. Comprehensive multigene testing shifted significantly; testing for ≥ 5 genes rose sharply from late 2021, followed by a marked increase in 6-7 gene testing from mid-2023. Testing for rare drivers (MET, RET, KRAS, HER2) increased substantially. However, approximately 30% of patients remained untested regardless of region or age. While the proportion of patients receiving first-line targeted therapy plateaued at just under 30%, the use of targeted therapies for rare drivers showed a steady increase. In conclusion, multigene testing has rapidly replaced single-gene testing in Japan, narrowing the diagnostic gap for rare oncogenic drivers. Nevertheless, the persistent 30% untested rate emphasizes the need for better shared decision-making to ensure all patients receive comprehensive biomarker evaluation.
