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Liver diseases constitute a major global health burden, contributing substantially to morbidity and mortality worldwide. Although effective therapeutic strategies have been developed for key risk factors, such as hepatitis C infection, therapeutic options for most other liver diseases remain limited. Noncoding RNAs (ncRNAs), which regulate diverse cellular and molecular processes, have emerged as promising therapeutic targets and biomarkers in liver diseases. In this study, we summarize the mechanisms of action and functional roles of ncRNAs, such as long ncRNAs (lncRNAs), circular RNAs (circRNAs), and PIWI–interacting RNAs (piRNAs), to improve therapeutic strategies and diagnostic precision in liver diseases, such as liver fibrosis and hepatocellular carcinoma (HCC).

Emerging evidence has demonstrated that PIWI-interacting RNAs (piRNAs) play important roles in various physiological processes and contribute to cancer progression. Moreover, piRNAs and PIWI protein levels are associated with the prognosis and chemoresistance of various cancers. The limitations of biomarkers challenge early detection and monitoring of chemoresistance and cancer relapse. To evaluate the potential of piRNA as a diagnostic biomarker in oncology, we systematically reviewed previous studies on the subject. PubMed, Embase, and Cochrane databases were searched to evaluate the diagnostic relevance of piRNAs in cancer. Eighteen studies (2,352 patients) were included. The quality of each study was evaluated with AMSTAR and QUADAS-2 tool. The area under the curve (AUC) values of 26 piRNAs in patients with cancer ranged from 0.624 to 0.978, with piR-9491 showing the highest value (0.978). The sensitivity of the total of 21 piRNAs in cancer patients was between 42.86 and 100, with piR-9491 showing the highest sensitivity (100). The specificity of these 21 piRNAs ranged from 60.10 to 96.67 (with piR-018569 showing the highest specificity (96.67)). Their odds ratios were between 1.61 and 44.67, and piR-12488 showed the highest odds ratio (44.67). Generally, the piRNAs in this review showed better sensitivity and AUC values than current clinical diagnostic biomarkers, although current biomarkers appear to be more specific. Reviewed piRNAs showed better diagnostic performance than currently used clinical biomarkers. Notably, piR-823 showed a significant diagnostic performance in four types of cancer (colorectal, esophageal, gastric, and renal cell cancer). However, all 18 studies included in this review were a case-control study. So, further prospective studies are required for their validation.

Glioblastoma is a diffusely growing malignant brain tumor and among the most aggressive of all tumors. Wilms' tumor 1‐associating protein (WTAP) is a nuclear protein that has been associated with regulation of proliferation and apoptosis. Although its dynamic expression and physiological functions in vascular cells have been reported, those in other cells are largely unknown. Here, we show for the first time that WTAP is overexpressed in glioblastoma. Moreover we found that WTAP regulates migration and invasion of glioblatoma cells. Specific knockdown by siRNA or overexpression by cDNA regulated migration and invasion of cancer cells. In xenograft study, WTAP overexpression made cancer cells more tumorigenic. In the investigation for its underlying mechanism, we found that the activity of epidermal growth factor receptor can be regulated by WTAP. These results reveal a novel function of WTAP and suggest its clinical application.

The development of physiologically relevant three-dimensional (3D) culture systems is essential for modeling tumor complexity and improving the translational impact of cancer research. We established a 3D in vitro model of human hepatocellular carcinoma (HCC) using a marine collagen peptide-based (MCP-B) biomimetic hydrogel scaffold optimized for multicellular spheroid growth. Compared with conventional two-dimensional (2D) cultures, the MCP-B hydrogel more accurately recapitulated native tumor biology while offering simplicity, reproducibility, bioactivity, and cost efficiency. HCC cells cultured in MCP-B hydrogel displayed tumor-associated behaviors, including enhanced proliferation, colony formation, migration, invasion, and chemoresistance, and enriched cancer stem cell (CSC) populations. Molecular analyses revealed upregulated expression of genes associated with multidrug resistance; stemness regulation and markers; epithelial–mesenchymal transition (EMT) transcription factors, markers, and effectors; growth factors and their receptors; and cancer progression. The spheroids also retained liver-specific functions, suppressed apoptotic signaling, and exhibited extracellular matrix remodeling signatures. Collectively, these findings demonstrate that the 3D HCC model using MCP-B hydrogel recapitulates key hallmarks of tumor biology and provides a robust, physiologically relevant platform for mechanistic studies of HCC and CSC biology. This model further holds translational value for preclinical drug screening and the development of novel anti-HCC and anti-CSC therapeutics.

UNC13 family (also known as Munc13) proteins are evolutionarily conserved proteins involved in the rapid and regulated secretion of vesicles, including synaptic vesicles and cytotoxic granules. Fast and regulated secretion at the neuronal and immunological synapses requires multiple steps, from the biogenesis of vesicles to membrane fusion, and a complex array of proteins for each step. Defects at these steps can lead to various genetic disorders. Recent studies have shown multiple roles of UNC13D in the secretion of cytotoxic granules by immune cells. Here, the molecular structure and detailed roles of UNC13D in the biogenesis, tethering, and priming of cytotoxic vesicles and in endoplasmic reticulum are summarized. Moreover, its association with immune diseases, including familial hemophagocytic lymphohistiocytosis type 3, macrophage activation syndrome, juvenile idiopathic arthritis, and autoimmune lymphoproliferative syndrome, is reviewed. Finally, the therapeutic application of CRISPR/Cas9-based gene therapy for genetic diseases is introduced.

Background Recycling of integrin via endosomal vesicles is critical for the migration of cancer cells, which leads to the metastasis of pancreatic cancer and devastating cancer-related death. So, new diagnostic and therapeutic molecules which target the recycling of endosomal vesicles need to be developed. Methods Public databases including TCGA, ICGC, GSE21501, GSE28735, and GENT are analyzed to derive diagnostic and therapeutic targets. To reveal biological roles and underlying mechanisms of molecular targets, various molecular biological experiments were conducted. Results First, we identified UNC13D’s overexpression in patients with pancreatic cancer (n = 824) and its prognostic significance and high hazard ratio (HR) in four independent pancreatic cancer cohorts (TCGA, n = 178, p  = 0.014, HR = 3.629; ICGC, n = 91, p  = 0.000, HR = 4.362; GSE21501, n = 102, p  = 0.002, HR = 2.339; GSE28735, n = 45, p  = 0.022, HR = 2.681). Additionally, its expression is associated with the clinicopathological progression of pancreatic cancer. Further biological studies have shown that UNC13D regulates the migration of pancreatic cancer cells by coupling the exocytosis of recycling endosomes with focal adhesion turnover via the regulation of FAK phosphorylation. Immunoprecipitation and immunocytochemistry showed the formation of the RAB11-UNC13D-FAK axis in endosomes during integrin recycling. We observed that UNC13D directly interacted with the FERM domain of FAK and regulated FAK phosphorylation in a calcium-dependent manner. Finally, we found co-expression of UNC13D and FAK showed the poorest survival (TCGA, p  = 0.000; ICGC, p  = 0.036; GSE28735, p  = 0.006). Conclusions We highlight that UNC13D, a novel prognostic factor, promotes pancreatic cancer progression by coupling integrin recycling with focal adhesion turnover via the RAB11-UNC13D-FAK axis for the migration of pancreatic cancer cells.

Polydopamine (PDA) surface coatings are widely used in biomedical engineering to enhance cell–substrate interactions; however, their effects on cancer-cell behavior remain unclear. In this study, we investigated how PDA-coated two-dimensional (2D) culture surfaces influence oncogenic traits of human prostate cancer (PC) cells in vitro. Using LNCaP, DU145, and PC3 cell lines, we found that PDA-coated substrates markedly increased the adhesion, migration, invasion, proliferation, and colony formation in a dose- and time-dependent manner. PDA exposure also induced epithelial–mesenchymal transition (EMT), upregulated cancer stem cell markers (CD44, CD117, CD133, Sox2, Oct4, and Nanog), and elevated expression of metastasis- and chemoresistance-associated molecules (MMP-2, MMP-9, MDR1, and MRP1). Mechanistically, PDA coatings enhanced integrin α2β1-associated cell adhesion, accompanied by increased focal adhesion kinase (FAK) phosphorylation and downstream activation of JNK signaling. Pharmacological inhibition of integrin α2β1 (BTT-3033), FAK (PF573228) and JNK (SP600125) effectively abrogated PDA-induced malignant phenotypes and restored chemosensitivity to cabazitaxel, cisplatin, docetaxel, curcumin, and enzalutamide. Collectively, these findings identify PDA-coated surfaces as a simple, efficient, and reductionist in vitro platform for studying adhesion-mediated signaling and phenotypic plasticity in PC cells, while acknowledging that further validation in three-dimensional (3D) and patient-derived models will be required to establish in vivo relevance.

The coatomer complex has been implicated in cancer progression; however, a comprehensive pan-cancer analysis is lacking. Therefore, it is essential to identify the critical roles and essentiality of coatomer genes across pan-cancer. We systematically profiled the genetic alterations, expression patterns, prognostic relevance, and functional dependencies of all coatomer subunits across multiple cancers using more than 10,000 tumor samples from The Cancer Genome Atlas, complemented by functional perturbation data from CRISPR (n = 1178) and RNAi (n = 707) screens in DepMap. Functional validation was also performed to identify the essentiality of selectively essential coatomer genes in hepatocellular carcinoma (HCC). Gene amplification, most notably of COPB2, was the most frequent alteration and was associated with poor survival in bladder and esophageal cancers. Mutations in COPA and SEC31A also demonstrated prognostic significance in endometrial carcinoma. Expression analyses revealed broad upregulation of coatomer genes across cancer types, with COPG1 and COPB1 emerging as strong risk-associated genes (HR > 2). Integrative functional dependency analyses identified COPG1 as selectively essential in multiple cancers, and its loss was associated with increased drug sensitivity. Functional validation in hepatocellular carcinoma revealed that COPG1 knockdown impaired malignant phenotypes and reduced tumorigenicity in vivo. Mechanistically, COPG1 depletion induced Golgi disruption and ER stress, increased ROS production, and suppressed PI3K–AKT signaling, thereby sensitizing cells to sorafenib and doxorubicin. Collectively, this pan-cancer analysis reveals the context-dependent roles of coatomer subunits and identifies COPG1 as a novel oncogenic driver and potential therapeutic target in HCC, mediating chemoresistance through redox modulation and PI3K–AKT pathway inhibition.

27-Hydroxycholesterol (27OHChol), a cholesterol metabolite, induces inflammatory responses in monocytic cells and promotes their differentiation into mature dendritic cells. Here, we examined whether inhibition of heat shock protein 90 (HSP90) modulates these responses. Treatment with ganetespib, a selective HSP90 inhibitor, significantly reduced chemokine CCL2 expression, lowering monocytic cell migration. It also suppressed matrix metalloproteinase-9 (MMP-9) expression and attenuated the lipopolysaccharide (LPS) response otherwise amplified by 27OHChol. Furthermore, ganetespib decreased mature dendritic cell markers (CD80, CD83, CD88) and restored endocytic activity, indicating a less activated state. These changes suggest that HSP90 regulates 27OHChol-induced pro-inflammatory activation via its client proteins. To explore this mechanism, we examined the phosphorylation status of signaling proteins. 27OHChol enhanced phosphorylation of Akt and its downstream targets, S6 and 4E-BP1 within the Akt/mTORC1 pathway. Ganetespib reduced total and phosphorylated Akt and 4E-BP1, and selectively inhibited S6 phosphorylation without altering total protein level. Collectively, these findings demonstrate that HSP90 inhibition by ganetespib mitigates 27OHChol-driven monocytic cell activation through suppression of the HSP90-Akt/mTORC1 axis. Targeting this pathway may provide a promising therapeutic strategy for metabolic inflammation associated with oxysterols.

Recently, the need to develop a robust three-dimensional (3D) cell culture system that serves as a valuable in vitro tumor model has been emphasized. This system should closely mimic the tumor growth behaviors observed in vivo and replicate the key elements and characteristics of human tumors for the effective discovery and development of anti-tumor therapeutics. Therefore, in this study, we developed an effective 3D in vitro model of human prostate cancer (PC) using a marine collagen-based biomimetic 3D scaffold. The model displayed distinctive molecular profiles and cellular properties compared with those of the 2D PC cell culture. This was evidenced by (1) increased cell proliferation, migration, invasion, colony formation, and chemoresistance; (2) upregulated expression of crucial multidrug-resistance- and cancer-stemness-related genes; (3) heightened expression of key molecules associated with malignant progressions, such as epithelial–mesenchymal transition transcription factors, Notch, matrix metalloproteinases, and pluripotency biomarkers; (4) robust enrichment of prostate cancer stem cells (CSCs); and (5) enhanced expression of integrins. These results suggest that our 3D in vitro PC model has the potential to serve as a research platform for studying PC and prostate CSC biology, as well as for screening novel therapies targeting PC and prostate CSCs.