Jar-Yi Ho

Therapeutic resistance remains a major challenge in bladder cancer, encompassing resistance to intravesical Bacillus Calmette–Guérin (BCG) therapy, platinum- and gemcitabine-based chemotherapy and immune-checkpoint blockade. Although extracellular vesicles (EVs) have been implicated in cancer drug resistance, their roles in bladder cancer are often discussed within the broader context of EV biology, making it difficult to distinguish direct mechanisms of treatment resistance from treatment-associated remodelling or biomarker associations. In this review, we refocus EV-mediated therapeutic resistance in bladder cancer and propose an evidence-stratified framework, distinguishing EVs as causal mediators, permissive amplifiers or biomarkers of drug adaptation. Studies have provided substantial mechanistic evidence from chemotherapy-associated models, including EV-mediated regulation of gemcitabine resistance through H3C14-associated EV remodelling and chemotherapy-exposed bladder cancer EVs that support stem-like, treatment-tolerant tumour states. Evidence supporting EV involvement in platinum resistance, BCG failure and immunotherapy resistance remains biologically plausible but less directly established. Therefore, clearer drug-specific models, improved EV-subtype resolution, cargo perturbation and functional rescue experiments are needed. We also discuss urinary EVs for longitudinal monitoring of treatment response and emerging resistance in bladder cancer. By integrating drug-specific therapeutic contexts with EV-specific causality criteria, this review provides a focused framework for evaluating when EVs mediate bladder cancer drug resistance, amplify adaptive tumour–microenvironment states or primarily serve as biomarkers for therapeutic monitoring.

Background: Psychological distress is an important component of cancer survivorship, particularly among patients undergoing radical cystectomy (RC) for bladder cancer. However, the prognostic significance of postoperative psychiatric medication exposure following RC remains unclear. Aims: To investigate the association between postoperative antidepressant and/or anxiolytic exposure and survival outcomes following RC for bladder cancer. Methods: This retrospective propensity score–matched cohort study used data from the TriNetX US Collaborative Network. Adult patients who underwent RC for bladder cancer (2005–2025) were identified. Postoperative psychiatric medication exposure was defined as new use of antidepressants (Anatomical Therapeutic Chemical: N06A) and/or anxiolytics (ATC: N05B). The primary analysis evaluated combined antidepressant/anxiolytic exposure, with separate antidepressant‐only and anxiolytic‐only subgroup analyses. Overall survival (OS) and all‐cause mortality were evaluated after 1:1 propensity score matching (PSM). Results: The primary analysis identified 2461 exposed and 7257 unexposed patients, yielding 1521 matched pairs after PSM. Patients exposed to postoperative psychiatric medication were associated with significantly poorer OS than their matched controls (hazard ratio [HR]: 1.377, 95% confidence interval [CI]: 1.261–1.502; log‐rank p < 0.001). Similar associations were observed in subgroup analyses. Antidepressant‐only exposure was associated with poorer OS (HR: 1.260, 95% CI: 1.161–1.367; p < 0.001), and the anxiolytic‐only subgroup demonstrated the strongest association with poorer survival (HR: 1.457, 95% CI: 1.324–1.604; p < 0.001). Conclusions: Psychiatric medication use may represent a clinically observable marker of psychological burden and survivorship vulnerability following RC. Early recognition of postoperative psychological vulnerability may facilitate timely psycho‐oncological support and multidisciplinary survivorship care following RC.

Cisplatin (cis-diamminedichloroplatinum(II) [DDP]) is a key chemotherapeutic agent for advanced endometrial cancer; however, chemoresistance substantially limits its clinical benefit. Extracellular vesicles (EVs) mediate intercellular communication and influence tumour cell behaviour and therapeutic response. We investigated whether mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) and natural killer cell-derived extracellular vesicles (NK-EVs) modulate cisplatin responsiveness in endometrial cancer cells (RL95-2 and HEC-1A). MSC-EVs and NK-EVs were isolated and characterised using nanoparticle tracking analysis, scanning electron microscopy, and EV marker profiling. MSC-EVs and NK-EVs reduced RL95-2 and HEC-1A cell viability in a dose-dependent manner, with MSC-EVs exhibiting substantial effects at lower particle concentrations. In a cisplatin-resistant HEC-1A (HEC-1A DDP-R) model, MSC-EVs were associated with greater reductions in cell viability under cisplatin treatment conditions, whereas NK-EVs showed comparatively modest effects. Mechanistic analyses demonstrated altered expression of apoptosis- and cell cycle–related proteins, including increased cleaved poly(ADP-ribose) polymerase and cleaved caspase-3 levels and reduced cyclin A and cyclin D1 expression following MSC-EV treatment. Annexin V-fluorescein isothiocyanate/propidium iodide flow cytometry demonstrated increased apoptotic cell populations after MSC-EV treatment, with MSC-EV + DDP co-treatment resulting in the highest apoptotic fraction in chemoresistant HEC-1A cells. Collectively, these findings indicate that MSC-EVs are associated with altered cellular responses to cisplatin in chemoresistant endometrial cancer cells, accompanied by changes in apoptosis-related protein expression, apoptotic cell populations, and cell-cycle regulators. Further investigation is required to determine their mechanistic role and therapeutic potential in overcoming chemoresistance.

Extracellular vesicles (EVs) are critical mediators of intercellular communication within the tumour microenvironment and play a significant role in drug resistance. We aimed to investigate the mechanisms underlying gemcitabine (GCB) resistance in bladder cancer. GCB‐resistant bladder cancer cells exhibited dysregulation of nucleoside‐metabolizing enzymes and transporters. Characterization of EV subpopulations derived from GCB‐resistant cells revealed their ability to transfer drug‐resistant phenotypes to naïve cancer cells by modulating intracellular levels of nucleoside metabolic proteins and transporters. Proteomic and transcriptomic analyses identified the histone protein H3.2 and its corresponding transcript, H3C14, as key regulators in the transmission of GCB resistance. Notably, H3C14 overexpression in resistant cells restored GCB sensitivity, whereas its knockdown induced GCB resistance. Rab27A‐mediated biogenesis and secretion emerged as a crucial mechanism regulating EV release and H3C14 excretion in GCB‐resistant cells. A specific EV subpopulation enriched in CD147 and LAMB1—referred to as Excretion EVs—carried H3.2 (H3C14) but did not induce GCB resistance in recipient cells, suggesting their primary role in eliminating proteins associated with tumour progression and drug resistance. These findings highlight the role of EV‐mediated H3C14 excretion in regulating GCB resistance and suggest potential therapeutic strategies targeting EV pathways to overcome drug resistance in bladder cancer.

Introduction: Osteoarthritis (OA), a leading cause of disability among the elderly, is characterized by progressive joint tissue destruction. Fucoidan, a sulfated polysaccharide with known anti-inflammatory and antioxidant properties, has been investigated for its potential to protect against interleukin-1 beta (IL-1β)-induced articular tissue damage. Methods: Human primary chondrocytes and synovial fibroblasts were pre-treated with 100 μg/mL fucoidan before stimulation with 1 ng/mL of IL-1β. The protective effects of fucoidan were assessed by measuring oxidative stress markers and catabolic enzyme levels. These in vitro findings were corroborated using a rat anterior cruciate ligament transection-induced OA model. To explore the underlying mechanisms, particularly the interaction between microRNAs (miRs) and heme oxygenase-1 (HO-1), five candidate miRs were identified in silico and experimentally validated. Luciferase reporter assays were used to confirm direct interactions. Results: Fucoidan exhibited protective effects against IL-1β-induced oxidative stress and catabolic processes in both chondrocytes and synovial fibroblasts, consistent with in vivo observations. Fucoidan treatment restored HO-1 expression while reducing inducible nitric oxide synthase and matrix metalloproteinase levels in IL-1β-stimulated cells. Notably, this study revealed that fucoidan modulates the miR-22/HO-1 pathway, a previously uncharacterized mechanism in OA. Specifically, miR-22 was upregulated by IL-1β and subsequently attenuated by fucoidan. Luciferase reporter assays confirmed a direct interaction between miR-22 and HO-1. Conclusion: The results demonstrate that fucoidan mitigates OA-related oxidative stress in chondrocytes and synovial fibroblasts through the novel modulation of the miR-22/HO-1 axis. The miR-22/HO-1 pathway represents a crucial therapeutic target for OA, and fucoidan may offer a promising therapeutic intervention.

Bladder cancer progression and metastasis have become major threats in clinical practice, increasing mortality and therapeutic refractoriness; recently, epigenetic dysregulation of epithelial-to-mesenchymal transition (EMT)-related signaling pathways has been explored. However, research in the fields of long noncoding RNA (lncRNA) and competing endogenous RNA (ceRNA) regulation in bladder cancer progression is just beginning. This study was designed to determine potential EMT-related ceRNA regulation in bladder cancer progression and elucidate the underlying mechanisms that provoke aggressiveness. After screening the intersection of bioinformatic pipelines, LINC02470 was identified as the most upregulated lncRNA during bladder cancer initiation and progression. Both in vitro and in vivo biological effects indicated that LINC02470 promotes bladder cancer cell viability, migration, invasion, and tumorigenicity. On a molecular level, miR-143-3p directly targets and reduces both LINC02470 and SMAD3 RNA expression. Therefore, the LINC02470–miR-143-3p–SMAD3 ceRNA axis rescues SMAD3 translation upon LINC02470 sponging miR-143-3p, and SMAD3 consequently activates the TGF-β-induced EMT process. In conclusion, this is the first study to demonstrate that LINC02470 plays a pivotally regulatory role in the promotion of TGF-β-induced EMT through the miR-143-3p/SMAD3 axis, thereby aggravating bladder cancer progression. Our study warrants further investigation of LINC02470 as an indicatively prognostic marker of bladder cancer.

Gemcitabine (GCB) resistance is a major issue in bladder cancer chemoresistance, but its underlying mechanism has not been determined. Epithelial-mesenchymal transition (EMT) has been shown to be comprehensively involved in GCB resistance in several other cancer types, but the direct connection between EMT and GCB remains unclear. This study was designed to elucidate the mechanism of EMT-related GCB resistance in bladder cancer and identify a potential phytochemical to modulate drug sensitivity. The biological effects of ellagic acid (EA) or its combined effects with GCB were compared in GCB-resistant cells and the GCB-sensitive line in terms of cell viability, apoptosis, motility, and in vivo tumorigenicity. The molecular regulation of EMT-related GCB resistance was evaluated at both the mRNA and protein expression levels. Our results indicated that TGF-β/Smad induced the overactivation of EMT in GCB-resistant cells and reduced the expression of GCB influx transporters (hCNT1 and hENT1). Moreover, ellagic acid (EA) inhibited the TGF-β signaling pathway both in vitro and in vivo by reducing Smad2, Smad3, and Smad4 expression and thereby resensitized GCB sensitivity. In conclusion, our results demonstrate that TGF-β/Smad-induced EMT contributes to GCB resistance in bladder cancer by reducing GCB influx and also elucidate the novel mechanisms of EA-mediated inhibition of TGF-β/Smad-induced EMT to overcome GCB resistance. Our study warrants further investigation of EA as an effective therapeutic adjuvant agent for overcoming GCB resistance in bladder cancer.

Exosomes are essential for several tumor progression-related processes, including the epithelial–mesenchymal transition (EMT). Long non-coding RNAs (lncRNAs) comprise a major group of exosomal components and regulate the neoplastic development of several cancer types; however, the progressive role of exosomal lncRNAs in bladder cancer have rarely been addressed. In this study, we identified two potential aggressiveness-promoting exosomal lncRNAs, LINC00960 and LINC02470. Exosomes derived from high-grade bladder cancer cells enhanced the viability, migration, invasion and clonogenicity of recipient low-grade bladder cancer cells and activated major EMT-upstream signaling pathways, including β-catenin signaling, Notch signaling, and Smad2/3 signaling pathways. Nevertheless, LINC00960 and LINC02470 were expressed at significantly higher levels in T24 and J82 cells and their secreted exosomes than in TSGH-8301 cells. Moreover, exosomes derived from LINC00960 knockdown or LINC02470 knockdown T24 cells significantly attenuated the ability of exosomes to promote cell aggressiveness and activate EMT-related signaling pathways in recipient TSGH-8301 cells. Our findings indicate that exosome-derived LINC00960 and LINC02470 from high-grade bladder cancer cells promote the malignant behaviors of recipient low-grade bladder cancer cells and induce EMT by upregulating β-catenin signaling, Notch signaling, and Smad2/3 signaling. Both lncRNAs may serve as potential liquid biomarkers for the prognostic surveillance of bladder cancer progression.

We aimed to elucidate whether and how BRCA1 mislocalization [including membranous nuclear (MN) forms and negative patterns] is associated with the occurrence and the prognosis of breast cancer in young Taiwanese women. A case-control study was carried out to enroll 84 patients with breast cancer and 81 patients with benign breast disease. The subcellular localization of BRCA1 was examined using immunofluorescent assays on fresh tissue touch-imprinting slides to classify staining results into diffuse nuclear (DN), MN, and negative staining. Genetic variations of BRCA1 nuclear localization/transportation-related sequences were analyzed by cDNA sequencing of both nuclear localization signals (NLS) and nuclear export signals (NES). The BRCA1 antibody was verified by two other published ones. Comparisons of immunofluorescent assay with immunohistochemical and H&E staining methods were also performed. BRCA1 mislocalization conferred a 3.13-fold [95% confidence interval (CI): 1.31-7.50] risk of developing breast cancer for the MN form and a 5.79-fold (95% CI:1.58-21.23) risk for BRCA1-negative cases compared with DN staining. However, no genetic variant was found in the NES or the NLS region of the BRCA1 gene. In terms of prognosis, BRCA1 mislocalization showed a 3.5-fold (95% CI: 1.20-10.09) increased risk of breast cancer death compared with DN staining after adjusting for tumor node metastasis stage. BRCA1 MN forms and BRCA1-negative patterns led to a higher risk of carcinogenesis and a poor prognosis of breast cancer. Such BRCA1 mislocalization may not be directly caused by the genetic effects of the NLS and NES domains, but stem from nongenetic modifications (such as epigenetic silencing).

Breast cancer-related mortality increases annually. The efficacy of current breast cancer treatments is limited, and they have numerous side effects and permit high recurrence. Patients with estrogen receptor (ER)-negative or triple-negative breast cancer are particularly difficult to treat. Treatment for this type of cancer is lacking, and its prognosis is poor, necessitating the search for alternative treatments. This study screened Chinese herb Hibiscus syriacus extracts and identified a novel anti-cancer drug for patients with ER-negative breast cancer. The inhibitory effects on cell viability and migration were evaluated for each compound, and the molecular regulatory effects were evaluated on both mRNA and protein levels. We found several triterpenoids including betulin (K02) and its derivatives (K03, K04, and K06) from H. syriacus inhibited human triple-negative breast cancer cell viability and migration but revealed smaller cytotoxic effects on normal mammalian epithelial cells. Betulin and its derivatives induced apoptosis by activating apoptosis-related genes. In addition, they activated p21 expression, which induced cell cycle arrest in breast cancer cells. Betulin (K02) and betulinic acid (K06) had stronger inhibitory effects on cell viability and migration than K03 and K04. H. syriacus extracts might inhibit breast cancer cell viability and induce apoptosis by activating p53 family regulated pathways and inhibiting AKT activation. H. syriacus extracts may provide important insight into the development of novel alternative therapies for breast cancer.