IUBMB Life最新文献

Malignant transformation is not merely the consequence of stochastic genetic mutations but rather a convergence of complex interplay between genetic, epigenetic, and environmental factors that collectively reprogram normal cells into cancerous ones. Central to these processes is the loss of tumor suppressor genes, activation of oncogenes, chromosomal instability, and widespread epigenetic remodeling. A pivotal aspect of this transformation involves the contribution of ncRNAs that have been recurrently implicated in malignant transformation. While much attention is directed toward miRNAs, circRNAs, and lncRNAs, piRNAs have remained comparatively overlooked in cancer biology. This is despite a growing body of evidence implicating piRNAs in regulating tumorigenic pathways, genomic stability, and epigenetic gene silencing. Our review explores the emerging role of the piRNAs and their regulatory protein PIWI in modulating key malignant features, including hyperproliferation, EMT, tumor evasion, migration, angiogenesis, and others. We also examine how this axis influences the initiation and progression of cancer, highlighting its potential to reshape established paradigms in cancer studies.

G-patch domain-containing protein 2 (GPATCH2), a member of the G-patch domain-containing family, has been implicated in tumor cell growth, but the link between GPATCH2 and hepatocellular carcinoma (HCC) remains uncertain. In the current study, comprehensive bioinformatics analysis revealed that GPATCH2 was markedly upregulated in HCC and positively correlated with aggressive clinicopathological features, including histologic grade, AFP, albumin level, and adjacent hepatic tissue inflammation, as well as miserable outcomes in HCC. GPATCH2 also has certain diagnostic value for HCC, histologic grade, and 1-, 3-, and 5-year survival outcomes. Functionally, loss-of-function experiments disclosed that silencing GPATCH2 suppressed HCC cell proliferation, migration, invasion, and xenograft tumor growth in the subcutaneous mouse model. Silencing GPATCH2 also resulted in an increase in the expression level of CDH1, while causing a decrease in the expression levels of FN1, TWIST1, SNAI1, and SNAI2. Rescue experiments further confirmed SNAI2 as a critical downstream effector mediating GPATCH2-driven oncogenic activity in HCC. Mechanistically, GPATCH2 was uncovered to be transcriptionally activated by the transcription factor Yin Yang 1 (YY1), and can mediate the role of YY1 in promoting HCC progression and elevating SNAI2 expression. Taken together, GPATCH2 is a YY1-regulated oncogenic driver that promotes HCC advancement through SNAI2, highlighting its potential as a diagnostic, prognostic, and therapeutic target for HCC.

Mitochondria, as the center of cellular energy metabolism, play multiple key roles in the progression of triple-negative breast cancer (TNBC). Mitochondrial fission regulator 1 (MTFR1) is a mitochondrial regulatory factor that plays a part in regulating mitochondrial fission and cell development. It is still unknown how MTFR1 functions in TNBC. We discovered MTFR1 to be a crucial gene in TNBC with clinical diagnostic value using database mining analysis. The effects of MTFR1 on TNBC cell proliferation, migration, invasion, and mitochondrial function were determined using the Cell Counting Kit-8, wound healing, and Transwell assays. Nude mouse models were established to explore the impact of MTFR1 on TNBC tumor growth and metastasis. Additionally, western blot and transcriptome sequencing (RNA-seq) were used to investigate the mechanism of MTFR1's involvement in TNBC progression. We used database extraction, WGCNA, Cox regression, and ROC (receiver operating characteristic) curve analysis to identify and confirm MTFR1 as a critical gene in TNBC. In TNBC patients, high MTFR1 expression is related to poor prognosis and diagnostic value. Knockdown of MTFR1 inhibits the proliferation and metastasis of TNBC cells and tumor bodies, affecting mitochondrial function. MTFR1 knockdown inhibits the growth, metastasis, and mitochondrial function of TNBC cells and tumors. Furthermore, transcriptome sequencing and western blot experiments confirmed that MTFR1 knockdown inhibits the activation of the NF-κB signaling pathway. In this study, we report for the first time that MTFR1 is a critical gene upregulated in TNBC. MTFR1 is an oncogene in TNBC and is involved in cell growth, migration, and mitochondrial function, and promotes TNBC progression through the NF-κB signaling pathway. Therefore, targeting MTFR1 may be a promising therapeutic target for TNBC patients.

A significant portion of fatalities from coronary artery disease (CAD) has been attributed to be primarily triggered by atherosclerosis. The melanoma inhibitory activity protein-3 (MIA3) gene has been found to be a key regulator for plaque stability in coronary artery atherosclerosis. Recent advances have unveiled the role of this gene in the formation of MIA3 protein, via which it potentially regulates the homeostatic circuit of various molecular proteins inside the cell and provides a safety profile to heart patients. Understanding how this gene exists, functions, signals, and can be targeted is therefore crucial to tackle the challenges in the field of cardiology. In this review, we have elaborated on its role in various cellular processes and several reported diseases to develop a holistic insight into the function of this gene. We have shown how this gene contributes to the budding of vesicles from the endoplasmic reticulum and helps in the transport of apolipoproteins and collagen to the exterior of the cell. We shed light on its role in the pathogenesis of CAD and also explain its role in other diseases involving bone mineralization or collagen defects. We explore the MIA3 gene at both genetic and protein levels and elaborate on its evolutionary conservation across species. In this paper, we also dissect the signaling mechanisms of the MIA3 gene inside the cell involving several protein interactions to form the COPII complex and initiate the vesicular budding at the endoplasmic reticulum. We also discuss the various therapeutic options that can target the MIA3 signaling pathway in several diseases, with a particular emphasis on CAD.

The rapid advancement of nanotechnology has ushered in a new era of biomedical innovation, where nanomaterials serve as powerful tools at the interface of tissue regeneration and targeted cancer therapy. This review explores the dual roles of nanomaterials in modulating biological responses, emphasizing their programmable and multifunctional nature. In tissue engineering, nanostructured scaffolds and cell-instructive surfaces recreate extracellular matrix cues, guiding stem cell behavior, promoting regeneration, and enabling organ-specific repair. Concurrently, in oncology, smart nanocarriers exploit tumor microenvironmental triggers-such as pH, redox gradients, or hypoxia-for precise drug delivery, reducing off-target effects and enhancing therapeutic outcomes. Next-generation platforms achieve dynamic control over cellular processes by integrating stimuli-responsive designs, immune modulation strategies, and mechano-sensitive systems. Furthermore, the convergence of regenerative and oncologic pathways-through shared signaling cascades, immune responses, and stem cell dynamics-demands a careful balance in nanoparticle programming to prevent unintended activation of malignant pathways. The review also highlights future directions, including intelligent, modular nanomaterials that synergize therapeutic, regenerative, and diagnostic capabilities. Collectively, these insights illuminate a path toward precision nanomedicine, where context-aware materials actively orchestrate healing or destruction with minimal collateral damage, transforming the future of personalized healthcare.

Chemoresistance remains a significant hurdle in breast cancer treatment. To address this, we explored the therapeutic potential of combining epirubicin, an anthracycline commonly associated with the development of resistance in cancer cells and with known cytotoxic effects, with 4-methylumbelliferone, a plant-derived coumarin. Our results demonstrated a coactive enhancement of epirubicin efficacy when this combination was applied to 3D breast cancer models, irrespective of molecular subtype. Mechanistically, 4-methylumbelliferone inhibits synthesis of hyaluronan, a key component of the tumor microenvironment that promotes tumor growth and metastasis. By disrupting hyaluronan production, this compound facilitated drug penetration into tumor spheroids and reduced the expression of drug efflux pumps, thereby increasing intracellular drug accumulation. Consequently, the combined treatment led to a significant reduction in cell viability and promotion of cell death. Our findings suggest that targeting hyaluronan metabolism in conjunction with conventional chemotherapy offers a promising strategy to overcome drug resistance in breast cancer. This drug repositioning approach not only improves treatment efficacy but also highlights the potential of targeting the tumor microenvironment to enhance cancer therapy. Further studies are warranted to elucidate the underlying mechanisms and to evaluate the clinical translation of this combination therapy.

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide, with drug resistance being a major challenge in limiting the available treatment options. This review focuses on the signaling pathways (Hedgehog, Hippo, Notch, Wnt/β-catenin, PI3K/Akt, and MAPK/ERK pathways) that are implicated in the development of drug resistance mechanisms in CRC, such as DNA repair systems, tumor microenvironments, autophagy, metabolic reprogramming, evasion of apoptosis, and efflux pumps. Furthermore, recent advancements in targeted and combinatorial diagnostic-therapeutic approaches are highlighted. This review delineates the significance of signaling cascades and their clinical relevance, offering novel perspectives on the formulation of therapeutic strategies to mitigate drug resistance. In light of the increasing prevalence of drug-resistant CRC and the lack of effective solutions, it addresses the persistent demand for improved therapeutic modalities and provides a comprehensive framework for forthcoming research in this domain.

Cell division cycle-associated protein 4 (CDCA4) has the potential to indicate lung adenocarcinoma (LUAD) development, but its regulatory role in mitophagy remains unclear. This study aimed to elucidate the mitophagy regulation and therapeutic implications of CDCA4 in LUAD. CDCA4 expression was significantly elevated in LUAD clinical specimens versus paracancerous tissues and inversely correlated with mitophagy activity. Lentiviral vectors were employed to manipulate established LUAD cells, followed by treatment with chloroquine (CQ; lysosomal inhibitor) and rapamycin (autophagy inducer) in CDCA4-silenced cells. CDCA4 knockdown elevated total and mitochondrial superoxide levels, disrupted mitochondrial membrane potential, activated the PINK1/Parkin pathway, enhanced LC3-II conversion, and degraded mitochondrial membrane proteins, collectively promoting mitophagy. Silencing CDCA4 suppressed malignant phenotypes (proliferation/migration), effects reversed by CQ but exacerbated by rapamycin. Mechanistically, CDCA4 interacted with SERTAD1 and E2F1 and stabilized these proteins. The promotion of mitophagy by CDCA4 silencing was impaired by the overexpression of SERTAD1 and E2F1. LUAD cells silencing CDCA4 were injected into immunodeficient mice for in vivo verification. CDCA4-silenced xenografts exhibited suppressed tumor growth, increased apoptosis, and elevated mitophagy-related markers. This study identifies the CDCA4/SERTAD1/E2F1 complex as a pivotal mitophagy-inhibitory hub in LUAD, proposing this axis as a novel predictive and therapeutic target.

This review introduces a novel conceptual framework, which suggests that key DNA functions, including rapid gene activation, conformational changes, and chromosomal structuring, could be regulated by an electronic-like circuit. The winding of strands around histones can also be attributed to an electronic effect. Many physiological processes are based on biomolecular electronic circuits and hinge on events of charge transfer. Mitochondria are recognized as the power source for cell functions, while the semiconductive properties of the nucleobases of DNA strands are controversial. Nuclear aggregates of polyamines (NAPs), supramolecular compounds formed by the interaction of polyamines (putrescine, spermidine, and spermine) with phosphate ions, are credible candidates to form hybrid structures with DNA, which support electron conduction. The final effect of their assembly is the formation of nanotubes that envelop the DNA and assist the strands in their functions. Furthermore, NAPs show the typical structure of an organic semiconductor, having an aromatic-like arrangement of their monomeric rings and a pseudo-phosphorene nanoribbon disposition of the phosphates located at their apical region. Our work should be considered innovative, since we point to these compounds as a key for a more complete understanding of cell nucleus physiology and as potential models for the development of organic electronic nanodevices.