酒井 康弘

Background/aim: Current clinicopathological factors inadequately capture the biological heterogeneity of non-muscle-invasive bladder cancer (NMIBC). This study investigated the prognostic significance of ubiquitin-like protein 3 (UBL3), a molecule involved in extracellular vesicle sorting and immune regulation, in NMIBC. Materials and methods: Following an exploratory analysis of public RNA-sequencing databases, we evaluated tissue samples from patients who underwent transurethral resection for primary NMIBC. A discovery cohort (n=37) was assessed for UBL3 mRNA via qRT-PCR and protein expression via immunohistochemistry (IHC) quantified using digital H-scores (QuPath). A separate internal validation cohort (n=192) was subsequently evaluated by IHC. The primary endpoint was recurrence-free survival (RFS). Results: The database analysis indicated that high UBL3 expression was associated with longer RFS in early-stage bladder cancer. In the discovery cohort, higher UBL3 mRNA levels were associated with prolonged RFS [hazard ratio (HR)=0.33, p=0.004]. mRNA levels also were associated with digital H-scores (ρ=0.39, p=0.018). In the separate internal validation cohort, elevated UBL3 protein expression was associated with a reduced risk of recurrence. A multivariable Cox regression confirmed that a higher UBL3 H-score (HR=0.95 per 10-point increase, p=0.023), alongside a negative preoperative urine cytology and immediate intravesical chemotherapy, remained independently associated with RFS. Conclusion: Elevated UBL3 expression was associated with prolonged RFS in patients with NMIBC following transurethral resection of bladder tumor. While UBL3 has potential as a prognostic biomarker, establishing its definitive clinical utility will require mechanistic investigations and validation across independent, multicenter cohorts.

Ameloblastoma (AB) is a benign yet locally aggressive odontogenic epithelial tumor, characterized by frequent recurrence and a potential for distant metastasis. The primary cilium (PC), a microtubule-based organelle that serves as a signaling hub for multiple oncogenic pathways, is typically reduced or absent in most human malignancies; however, its status in AB remains poorly defined. In this retrospective, tissue-based observational study, we investigated the presence of PC in 42 AB cases, encompassing all major histological subtypes, using immunohistochemistry, immunofluorescence, and ultrastructural techniques. As a comparator, 41 cases of oral squamous cell carcinoma (OSCC), a tumor originating from the same oral cavity region, were also analyzed. PC were consistently detected in all ABs but were absent in OSCCs. In ABs, the presence of PC was validated by multiple markers and imaging modalities. In conventional AB, the density of PC varies significantly among the histological patterns. Notably, the cilia frequently exhibited a polarized orientation in the peripheral columnar cells of the follicular subtype. PC were also present in recurrent and metastatic lesions, although their significance in disease progression remains uncertain. Elevated GLI1 mRNA expression, nuclear accumulation of GLI1, and elevated SHH mRNA and protein expression indicated the activation of the Hh signaling pathway in ABs. Transcriptomic screening of early ciliogenesis-related genes revealed selective upregulation of CEP164 in ABs but not in OSCCs or other PC-deficient carcinomas. CEP164 protein was significantly overexpressed and localized closely apposed to but only partially overlapped with γ-tubulin signals, consistent with its role at the distal appendages of the basal body. Functional analyses demonstrated that CEP164 overexpression promoted PC formation, whereas its knockdown suppressed ciliogenesis. These findings indicate that ABs uniquely preserve functional PC and implicate CEP164 as a key mediator of this phenotype, offering novel insights into AB biology and highlighting its potential as a diagnostic and therapeutic target.

Cancer genome testing routinely reports driver alterations, mutational signatures, and DNA repair states, yet key clinical phenotypes—tumor behavior, relapse risk, and chemoresistance—are not fully explained by geno- type alone. Deleted in split-hand/split-foot 1 (DSS1) is a small, acidic, intrinsically disordered protein conserved across eukaryotes and shared by several large multiprotein assemblies, making it a plausible functional modifier of these phenotypes. This review summarizes DSS1 biology from the perspective of clinical laboratory medi- cine, focusing on how DSS1 links RNA metabolism, R-loop homeostasis, and homologous recombination repair (HRR) and how this linkage may inform biomarker development. Mechanistically, DSS1 behaves as a stabilizing “molecular glue” in protein complexes and serves as a core component of RNA export/quality-control modules, including TREX-2 and the TREX-2.1/REX complex, which regulate co-transcriptional messenger ribonucleop- rotein remodeling, nuclear export, and RNA surveillance—processes closely tied to R-loop (DNA:RNA hybrid) control and transcription-coupled DNA damage. DSS1 is also an obligate cofactor of BRCA2: DSS1 binding sta- bilizes BRCA2, improves its solubility, and limits off-target interactions, supporting repair-competent BRCA2 in the nucleus. We then review clinicopathological evidence that DSS1 dysregulation correlates with cancer behav- ior, including shorter relapse-free survival and a chemoresistant phenotype. Finally, we propose that DSS1-low, BRCA-proficient tumors may acquire BRCAness, providing a rationale for PARP inhibitor responses beyond cur- rent BRCA-focused companion diagnostics, and we outline how standardized DSS1 measurement (mRNA and/ or protein), integrated with BRCA status and other HRR-related signatures, could refine molecular testing and therapeutic stratification in routine practice.

Accurate distinction between pulmonary metastases of oral squamous cell carcinoma (OSCC) and primary lung squamous cell carcinoma (LSCC) is critical for clinical management, but practical immunohistochemical markers remain limited in routine practice. We screened three public mRNA expression datasets, GSE84846 for OSCC and The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium for LSCC, and selected six candidate markers for immunohistochemical evaluation in 39 OSCC and 92 LSCC specimens. Among them, keratin 1 (K1; encoded by KRT1) and keratin 18 (K18; encoded by KRT18) showed the most significant differential expression between OSCC and LSCC (both p < 0.0001). K1 was predominantly expressed in OSCC and rarely in LSCC, whereas K18 showed the opposite pattern. K1 showed high specificity (0.989) and an odds ratio of 117.8, while K18 showed a specificity of 0.974 and an odds ratio of 59.1. Receiver operating characteristic analysis confirmed strong discriminatory performance for K1 (AUC, 0.865) and K18 (AUC, 0.872). In four whole-exome sequencing-confirmed pairs of primary OSCC and lung metastases, staining patterns for both markers were concordant between the primary oral tumors and pulmonary lesions. These findings support K1 and K18 as practical markers for distinguishing pulmonary metastases of OSCC from primary LSCC.

Prospero homeobox protein 1 (PROX1) is aberrantly expressed in tumors, including neuroendocrine neoplasms (NENs); however, the detailed expression pattern remains elusive. This study aimed to immunohistochemically assess PROX1 expression. Immunohistochemistry (IHC) for PROX1 was performed on tissue microarrays of normal tissues (n = 107), NENs (n = 152) (small cell lung carcinoma [SCLC], lung carcinoid [LC], gastroenteropancreatic-NEN [GEP-NEN], esophageal neuroendocrine carcinoma [ENEC], medullary thyroid carcinoma [MTC], neuroblastoma [NB], and pheochromocytoma [PHEO]), and non-NENs (n = 469). In normal tissues, PROX1 was expressed in lymphatic endothelial cells and a subset of epithelial cells in the gastrointestinal tract and the distal convoluted tubules. In NENs, the positive expression was observed in the nucleus of tumor cells in 19/26 SCLC (73.1%), 13/16 LC (81.3%), 10/15 GEP-NEN (66.7%), 2/2 ENEC (100%), 17/43 MTC (39.5%), 1/25 NB (4.0%), and 0/25 PHEO (0%). Although PROX1 was negative in many non-NENs, our analysis revealed high expression in certain cases with medulloblastoma and one case with juvenile granulosa cell tumor. PROX1 was expressed in specific cases with epithelial NENs and some cases with non-NENs. Analysis of PROX1 should provide insights into the molecular characteristics of distinct tumors.