Clonal dispersal, resulting from the intermingling of tumor cell subpopulations, is thought to be a key driver of tumor heterogeneity. Despite advances in spatial modeling of cancer biology, quantification of clonal dispersal has been challenging. This study introduces a straightforward method, relying on fluorescent cell barcoding, to quantify clonal dispersal in various in vitro and in vivo models of colorectal cancer (CRC). Our approach allows for precise localization of clones and uncovering the degree of clonal mixing across different CRC models. Our findings suggest that clonal dispersal is correlated with the expression of genes involved in epithelial-mesenchymal transition and CMS4-related signaling pathways. We further identify a dispersal gene signature, associated with intratumor heterogeneity, which is a robust clinical predictor of poor prognosis and recurrence in CRC, highlighting its potential as a prognostic marker and a putative direction for therapeutic targeting.

Colon adenocarcinoma (COAD) is a leading cause of cancer mortality, with Aquaporin 9 (AQP9) implicated in its progression. M2 macrophages in the tumor microenvironment (TME) promote cancer metastasis, but the role of AQP9 on M2 macrophages remains unelucidated.

Using COAD cell lines, AQP9 expression was analyzed via RT-qPCR and Western blot (WB). Hypoxic conditions were simulated to assess HIF-1α and AQP9 interactions through ChIP and dual-luciferase assays. AQP9 knockdown effects on proliferation/migration were tested via colony formation and wound healing. M2 macrophage polarization and CD8+ T cell cytotoxicity were evaluated using flow cytometry, ELISA, and IHC in co-culture systems.

AQP9 was upregulated in COAD and correlated with poor prognosis. After AQP9 in COAD cells was knocked down, the abilities of tumor cells to migrate and proliferate were dampened. Hypoxia upregulated HIF-1α, which transcriptionally activated AQP9. Knocking down AQP9 repressed the M2 polarization of macrophages, thereby reinforcing the cytotoxicity of CD8+ T cells. No adverse events were reported in vitro.

AQP9 promotes COAD progression by driving HIF-1α-mediated M2 polarization, impairing CD8+ T cell function. Key limitations include the lack of in vivo validation and clinical cohort analysis.

Mounting research indicates that circRNAs are pivotal elements in tumorigenesis and progression. Understanding the mechanisms by which circRNAs function in tumors is crucial for identifying undiscovered diagnostic and treatment targets. This research centers on unraveling the mechanisms by which the novel circRNA, circFADS1, influences hepatocellular carcinoma (HCC) progression. CircFADS1 shows elevated expression in HCC and is linked to unfavorable prognosis. Functionally, circFADS1 overexpression accelerates HCC progression through inducing HCC proliferation and inhibited apoptosis. Mechanistically, RNA-seq analysis demonstrates its connection to the Wnt/β-catenin pathway. Moreover, circFADS1 interacts with GSK3β and promotes its ubiquitination and degradation by recruiting the ubiquitin ligase RNF114 while EIF4A3 facilitates the biogenesis of circFADS1. Additionally, circFADS1 is closely linked to lenvatinib resistance. Overall, this study reveals that circFADS1 regulates GSK3β function, influencing the progression of hepatocellular carcinoma. The EIF4A3/circFADS1/GSK3β/β-catenin axis is discovered to hold promise as a novel therapeutic target for hepatocellular carcinoma, while circFADS1 is also a significant factor in lenvatinib resistance.

Vascular remodeling represents a pathological basis for myocardial pathologies, including myocardial hypertrophy and myocardial infarction, which can ultimately lead to heart failure. The molecular mechanism of angiotensin II (Ang II)-induced vascular remodeling following myocardial infarction reperfusion is complex and not yet fully understood. In this study, we examined the effect of Ang II infusion on cardiac vascular remodeling in mice. Single-cell sequencing showed Ang II induced cytoskeletal pathway enrichment and that FOS like-1 (FOSL1) affected mouse cardiac endothelial dysfunction by pseudotime analysis. Myosin heavy chain 9 (MYH9) was predominantly expressed in primary cardiac endothelial cells. The Ang II type I receptor blocker telmisartan and the protein kinase C inhibitor staurosporine suppressed Ang II-induced upregulation of MYH9 and FOSL1 phosphorylation in human umbilical vein endothelial cells. Silencing MYH9 abolished Ang II-mediated inhibition of angiogenesis in human umbilical vein endothelial cells, and attenuated AngII-induced vascular hyperpermeability. We found that FOSL1 directly bound to the MYH9 promoter and thus activated transcription of MYH9 by the dual luciferase reporter and chromatin immunoprecipitation assays, leading to vascular dysfunction. In vivo, 6 weeks after injecting adeno-associated virus-ENT carrying the TEK tyrosine kinase (tie) promoter-driven short hairpin RNA for silencing FOSL1 (AAV-tie-shFOSL1), cardiac function represented by the ejection fraction and fractional shortening was improved, myocardial fibrosis was decreased, protein levels of phosphorylated FOSL1, MYH9, and collagen type I alpha were reduced, and cardiac vascular density was recovered in mice with endothelial Fosl1-specific knockdown in Ang II-infused mice. In ischemia-reperfusion mice, AAV-shFosl1 mice had a reduced infarct size and preserved cardiac function compared with control AAV mice. Our findings suggest a critical role of the FOSL1/MYH9 axis in hindering Ang II-induced vascular remodeling, and we identified FOSL1 as a potential therapeutic target in endothelial cell injuries induced by myocardial ischemia-reperfusion.

Although hepatitis B virus (HBV) infection is a well-documented etiologic factor for hepatocellular carcinoma (HCC), which ranks as the third leading cause of cancer-related mortality globally, the mechanism by which HBV facilitates cancer development remains largely elusive. In this study, we employed advanced methodologies including, single-cell RNA sequencing, flow cytometry, western blot analysis, chromatin immunoprecipitation-qPCR and Cut&Tag to investigate the expression of DTL and its biological functions in HCC. We observed that DTL is overexpressed in HBV-positive HCC samples, with its elevated expression being associated with increased tumor cell proliferation and reduced overall and disease-free survival rates. The upregulation of DTL expression was specifically induced by the HBV regulatory protein HBx, thereby substantiating the oncogenic potential of HBV. Mechanistically, our findings indicated that the HBx protein augments DTL transcription by binding to its promoter region, subsequently facilitating HCC cell proliferation and modulating cell cycle progression, particularly by increasing the proportion of cells in the S phase. Furthermore, DTL was identified as a protein that interacts with HBx and associates with the Cullin4-RING ubiquitin ligases (CRL4s), thereby stabilizing HBx by reducing its ubiquitin-mediated degradation. In vivo experiments demonstrated that DTL not only facilitated cancer cell proliferation by modulating the cell cycle but also promoted tumorigenesis in nude mice. Moreover, DTL expression modifies the tumor immune microenvironment by increasing the proportion of regulatory T cells, thereby contributing to immune evasion. In summary, our findings underscore the pivotal role of DTL as a key regulator in HBV-related HCC by influencing cell cycle progression and establishing a positive feedback loop involving the HBx-DTL-CRL4s. These insights expand our understanding of HBV oncogenic mechanisms and suggest that DTL could serve as a novel biomarker and therapeutic target, potentially enhancing patient outcomes.

Hepatitis B protein x (HBx) is considered a critical contributor to hepatitis B virus (HBV)‑associated liver cancer development. Protein regulator of cytokinesis 1 (PRC1) has been implicated in hepatocarcinogenesis. However, the clinical relevance, biological functions and related regulatory mechanisms of PRC1 in HBV‑associated liver cancer have not yet been clarified. PRC1 expression profiles in liver cancer were obtained from The Cancer Genome Atlas and Gene Expression Profiling Interactive Analysis database and through reverse transcription‑quantitative polymerase chain reaction and immunohistochemistry assays. A series of in vitro and in vivo assays were used to explore the function of the PRC1 gene and the possible mechanisms through which it affects HBV‑associated liver cancer. PRC1 was overexpressed in HBV‑positive liver cancer tissues. Functional studies in vitro demonstrated that HBx induced the expression of the PRC1 gene, which promoted cell autophagy and enhanced viability, invasion and migration. Furthermore, the knockdown of the PRC1 gene or treatment with the autophagosome inhibitor 3‑methyladenine blocked the HBx‑induced autophagic flux, disrupted the formation of autophagosomes, and promoted cell apoptosis. Liver cancer xenograft animal model experiments revealed that inhibition of autophagy by 3‑methyladenine or silencing of the PRC1 gene attenuated HBx‑induced malignant behavior in vivo. The absence of autophagy inhibited the expression of Bcl‑2, induced the expression of Bax, and regulated the levels of Th1 and Th2 cytokines. These results elucidate a mechanism wherein the PRC1 gene participates in the occurrence and development of HBV‑associated liver cancer by modulating autophagy. PRC1 could be a potential therapeutic target for liver cancer.

Cancer stem cells (CSCs) are significant factors in the treatment resistance and recurrence of glioblastoma. Chromobox protein homolog 7 (CBX7) can inhibit the progression of various tumors, but its impact on the stem cell-like properties of glioblastoma cells remains unclear. Clinically, low levels of CBX7 are associated with poor prognosis and increased distant metastasis in glioblastoma patients, and this low expression is caused by methylation of the CBX7 promoter. Our current research indicates that CBX7 plays a key role in suppressing the stem-like phenotype of glioblastoma. In this study, through bioinformatics analysis, we found that CBX7 is the most significantly downregulated member of the CBX family in glioblastoma and is closely associated with the stem-like phenotype of glioblastoma cells. We show that CBX7 promotes the degradation of myosin heavy chain 9 (MYH9) protein through the ubiquitin-proteasome pathway via the polycomb repressive complex 1 (PRC1) and suppresses the stem-like phenotype of glioblastoma cells by inhibiting the nuclear factor kappa-B (NF-κB) signaling pathway. Furthermore, overexpression of MYH9 in glioblastoma cells reverses the inhibitory effects of CBX7 on migration, proliferation, invasion, and stemness of glioblastoma cells. In summary, CBX7 acts as a tumor suppressor by inhibiting the stem cell-like characteristics of glioblastoma. The CBX7-MYH9-NF-κB signaling axis may serve as a potential therapeutic target for glioblastoma.

Stimulator of interferon response cGAMP interactor 1 (STING1), as an innate immune adaptor protein that mediates DNA sensing, has attracted tremendous biomedical interest. However, several recent researches have revealed the key role of STING1 in regulating the metabolic pathway. Here, we investigated its role in adipocyte differentiation. Preadipocytes with lentivirus-mediated Sting1 knockdown or overexpression were constructed to examine the effect of STING1 on adipocyte differentiation in vitro. Proteomics was performed in adipocytes to explore the mechanisms by which STING1 exerts pro-adipogenesis effects. Coimmunoprecipitation (CoIP)/mass spectrometry (MS) assay were used to identify the interacting partners of STING1. Our results showed that STING1 was upregulated during adipogenic differentiation of 3T3-L1 and white adipose tissue-derived stromal vascular precursor cells (WAT-SVF), accompanied by upregulation of adipocyte marker genes, peroxisome proliferator-activated receptor gamma (Pparg) and CCAAT/enhancer-binding protein beta (Cebpβ). Knockdown or overexpression of Sting1 altered adipogenesis in adipocytes. Mechanistically, proteomics and CoIP/MS assay revealed that STING1 targets non-muscle myosin protein (MYH9) to block its expression, which enhances AKT/GSK3β signaling and mediates β-catenin accumulation, affecting adipogenesis-related genes in adipocytes. These findings suggest that STING1 targeting combined with MYH9 regulates adipocyte differentiation through the AKT/GSK3β/β-catenin pathway. This is a new potential target for the treatment of hypertrophic adipose tissue, or obesity.

Disulfidptosis, a recently identified cell death mechanism, plays a pivotal role in the development, progression, and treatment of digestive tract tumors, including gastric cancer, hepatocellular cancer, esophageal cancer, colorectal cancer, pancreatic cancer, cholangiocarcinoma, and neuroendocrine tumors, which have high global incidence and mortality rates. Analyzing the expression of disulfidptosis-related gene expression within the tumor microenvironment enhances our understanding of tumor biology and facilitates novel diagnostic and therapeutic strategies. Research on immune infiltration and checkpoints can identify therapeutic targets linked to disulfidptosis, thereby improving immunotherapy efficacy. Targeting genes such as SLC7A11, which are essential for maintaining glutathione levels and regulating oxidative stress, may overcome chemoresistance and enhance existing treatments. Disulfidptosis could complement current therapies as it induces cytoskeletal collapse and selective tumor cell death, especially in chemoresistant cancers. Additionally, genes like SLC7A11, RPN1, and NCKAP1 in gastric cancer correlate with poor prognosis, highlighting their potential as prognostic biomarkers. Personalized medicine approaches utilizing disulfidptosis-related biomarkers could identify patients who would benefit from therapies targeting oxidative stress regulation, leading to more precise treatments and improved outcomes. This review summarizes disulfidptosis mechanisms, advancements in digestive cancers, and the potential of related genes for prognosis, immune response evaluation, and targeted therapies, providing novel perspectives for diagnosis and personalized treatment.

Epithelial‒mesenchymal transition (EMT) is a process in which polar epithelial cells transform into active mesenchymal cells and acquire invasion and migration capabilities (Cano CE, Motoo Y, Iovanna JL in Sci World J 10, 2010). EMT is involved in multiple physiological and pathological processes in the human body. The occurrence of EMT involves many signal transduction pathways and complex molecular mechanisms related to calnexin, growth factors, transcription factors, and the microenvironment. EMT is closely related to the invasion and metastasis of tumour cells. The MYH9 gene is closely associated with tumour progression. However, the function and regulatory mechanism of MYH9 in tumour occurrence and development remain unclear. Herein, we revealed for the first time that the migration, invasion, and metastatic abilities of glioma cells decreased significantly after MYH9 expression was downregulated. Moreover, our results suggested that MYH9 regulated the epithelial‒mesenchymal transition (EMT) process in glioma cells via β-catenin. In this mechanism, MYH9 was shown to bind to β-catenin and to increase its protein level by recruiting the deubiquitinase USP2 to form a complex. This complex suppressed β-catenin protein degradation, ultimately enhancing EMT signal transduction. This MYH9/β-catenin/EMT pathway represents a new molecular mechanism involved in the invasion promotion in gliomas. Our findings also demonstrated that MYH9 was crucial for inducing glioma cell migration. In summary, we suggest that MYH9 is a potential molecular marker for predicting tumour progression and prognosis and highlight its role in a new molecular mechanism of tumour metastasis.

Hepatitis B virus (HBV) infection contributes to hepatocellular carcinoma (HCC) tumorigenesis, drug resistance, and recurrence, although the underlying molecular mechanisms remain unclear. Recent studies suggest that HBV infection may be associated with liver cancer stem cells (LCSCs), but the exact mechanisms are yet to be resolved. In this study, we aimed to analyze the role of HBV infection in regulating the stemness of HCCs, which is closely linked to drug resistance.

Sphere formation assay and real-time Polymerase Chain Reaction quantification were used to isolate and confirm liver cancer stem cells. The inhibitory concentration values of sorafenib and regorafenib were calculated and compared using the Cell Counting Kit-8 assay. HBV infection was used to assess the effect of HBV replication on LCSC markers. Co-immunoprecipitation assay was performed to detect the interaction between CD133 and SRC. Furthermore, we utilized the CRISPR-Cas9 system to knockout CD133 expression in HepG2.2.15 cells.

LCSCs derived from HCCs exhibited high expression of stem cell markers and demonstrated reduced sensitivity to sorafenib and regorafenib. HBV replication promoted both drug resistance and stemness in hepatoma cells and clinical samples. Overexpression of HBx protein in HepG2 cells upregulated the expression of CD133, EpCAM, and CD24, enhancing resistance to sorafenib and regorafenib. Knockout of CD133 expression using the CRISPR-Cas9 system significantly inhibited drug resistance to both sorafenib and regorafenib in HepG2.2.15 cells. Mechanistically, HBV replication promoted CD133 expression, which in turn interacted with the SRC/STAT3 signaling pathway.

Our data suggest that HBV replication enhances the stemness and drug resistance of HCC, providing a strong theoretical foundation for the development of targeted and efficient treatments for HBV-infected HCCs.

Cyclin D3 (CCND3), a member of the cyclin D family, is known to promote cell cycle transition. In this study, we found that CCND3 was downregulated in cisplatin-resistant (cis-diamminedichloroplatinum, DDP) lung adenocarcinoma (LUAD) cells. The loss of CCND3 indeed impeded cell cycle transition. Unexpectedly, its downregulation significantly triggered cytoskeleton remodeling and chemoresistance and accelerated LUAD metastasis in vivo and in vitro. Moreover, the clinical samples showed a significant negative correlation between CCND3 expression and lymphatic metastasis, as well as the unfavorable survival prognosis of patients with LUAD. Mechanistically, CCND3 downregulation in DDP-resistant LUAD cells was attributable to the transcriptional suppression of PI3K/Akt/c-Jun signaling. Reduced CCND3 expression diminished the recruitment of the E3 ubiquitin ligase PARK2 to ubiquitinate and degrade the vimentin protein, thus triggering epithelial-mesenchymal transition (EMT) to result in cytoskeleton remodeling-stimulated metastasis and chemotherapeutic resistance in LUAD. These results demonstrated that activated PI3K/Akt/c-Jun significantly suppressed CCND3 expression, thereby inhibiting vimentin degradation via PARK2-mediated ubiquitination in DDP-resistant LUAD cells. This, in turn, promoted EMT, facilitating cytoskeleton remodeling-stimulated metastasis and chemoresistance to DDP. Overall, these findings provided a new perspective on the role of CCND3 in LUAD progression and acquired cisplatin resistance.

The incidence and development of various tumors, such as hepatocellular carcinoma (HCC), are linked to tumor stem cells. Although research has revealed how important SCL/TAL1 interruption site (STIL) is in many human tumors, the impact of STIL on HCC stem cells is poorly understood. This study aimed to examine the regulatory mechanisms and the function of STIL in the stemness of HCC tumor cells. Bioinformatics analysis was applied to determine the STIL and regulatory factor X-5 (RFX5) expression in HCC tissues. Immunohistochemistry (IHC) was used to detect the expression of STIL and RFX5 in HCC tissues. Quantitative real-time polymerase chain reaction was utilized to measure the STIL and RFX5 expression levels in HCC cells. The viability of the cells was assessed by the Cell Counting Kit-8 assay. The sphere formation assay was used to evaluate the sphere-forming capacity. The expression levels of the stem cell markers SOX2, Oct-4, CD133, CD44, the glycolysis-related proteins LDHA, HK2, AKT, p-AKT, and β-catenin were assessed by Western blot. Lactate production, oxygen consumption rate, and extracellular acidification rate were measured to assess the glycolytic capacity of HCC cells. Chromatin immunoprecipitation and dual-luciferase experiments were performed to validate the connection between RFX5 and STIL. Bioinformatics analysis determined that STIL exhibited high expression in HCC tissues and was enriched in the glycolysis pathway. In addition, the expression of glycolysis marker genes was positively correlated with STIL expression. Cell experiments verified that the activation of the glycolysis pathway by overexpression of STIL promoted stemness in HCC. Molecular experiments also revealed the binding relationship between STIL and RFX5. IHC detected high expression of STIL and RFX5 in HCC tissues. Cell functional experiments revealed that RFX5 could influence the HCC cells stemness by activating the STIL transcription via the glycolysis pathway. This study identified a novel role for the RFX5/STIL axis in HCC progression, which may offer treatment targets for HCC.

The mitotic kinase Aurora kinase A (AURKA), which plays a crucial role in cell cycle progression, represents a promising target for the treatment of colorectal cancer (CRC). Here, we found that AURKA is a target of a CRC suppressor, the Palmatine (PAL). However, the underlying mechanism remains elusive. This work aims to investigate the underlying mechanism how PAL suppresses CRC through AURKA. It was confirmed that AURKA played an important role in the development of CRC tumors through an Azoxymethane/Dextran sulfate sodium salt induced mice model and tissue microarrays of CRC-patients. Overexpression of AURKA was able to partially reverse the inhibitory effect of PAL on CRC cells, showing that PAL significantly inhibited the malignant phenotype and induced the G2/M phase arrest of CRC cells by down-regulating AURKA. Functional studies indicated that PAL attenuated the stability of AURKA protein and reduced its nuclear level, resulting in reduction of key proteins in the G2/M phase. Importantly, Co-IP and WB experiments suggested that Myosin heavy chain 9 (MYH9) interacted with AURKA and had an impact on its nuclear localization. PAL can decrease nuclear AURKA by reducing the interaction of AURKA and MYH9. Taken together, our study revealed that MYH9 as an auxiliary protein for the nuclear localization of AURKA and elucidated the mechanism that PAL reduced nuclear AURKA through inhibiting the interaction of AURKA and MYH9 to induce G2/M phase arrest in CRC cells. Therefore, this study may provide a theoretical basis of PAL for the treatment of CRC.

Ginseng-containing Shentao Ruangan granules (STR) have been a well-known Chinese medicine prescription for the treatment of hepatocellular carcinoma (HCC) in China for decades. This study aimed to establish an in silico experimental framework to decipher the underlying mechanism of STR in the treatment of HCC. Microarray analysis, network pharmacology, RNA-sequencing (RNA-seq), bioinformatics analysis, and in vivo and in vitro experiments were used as integrated approaches to uncover the effects and mechanisms of action of STR. The introduction of STR significantly suppresses the proliferation and metastasis of HepG2 and Huh7 cells. STR treatment notably suppressed the growth of transplanted Huh7 tumors. Furthermore, STR administration reduced the expression of various epithelial-to-mesenchymal transition (EMT)-related proteins including N-cadherin, vimentin, and [Formula: see text]-catenin. By employing a systems biology approach, 21 common genes were identified across RNA-seq data, TCGA-HCC dataset, and network pharmacology analysis. Finally, of these genes nine were found to be associated with both OS and PFS in patients with HCC within the TCGA cohort. Validation of candidate genes by qPCR and WB identified a significant downregulation in the expression of pGSK3[Formula: see text] and RELA protein with increasing concentrations of STR. These results elucidated the mechanism by which STR inhibits tumor growth and EMT of HCC may be related to the GSK3[Formula: see text]/RELA pathway.

Hepatocellular carcinoma (HCC) is the most prevalent malignant tumor, characterized by a poor prognosis. In recent decades, both the incidence and mortality rates of HCC have risen sharply. Sorafenib has emerged as the first conventional drug approved by the US Food and Drug Administration for first-line treatment in advanced HCC patients due to its favorable safety profile. However, its effectiveness is severely hindered by acquired drug resistance, which leads to only approximately 30% of HCC patients benefited from sorafenib therapy. Sorafenib resistance involves various mechanisms that inhibit cellular uptake of iron and reactive oxygen species (ROS). Consequently, ferroptosis a novel form of cell death contingent upon the accumulation of intracellular iron and ROS plays a critical role in mediating sorafenib resistance through the Hippo YAP pathway or Keap1-Nrf2 system. This review aimed to comprehensively elucidate the mechanisms underlying sorafenib resistance in HCC, particularly focusing on ferroptosis and its pathways, to provide valuable insights into targeting ferroptosis or its pathways for sorafenib-resistant HCC treatment.

This study aimed to investigate the influence of sperm miRNAs on fertilization rates (FR) in in vitro fertilization (IVF) and to explore potential regulatory mechanisms in sperm-mediated fertilization and embryo development. Through high-throughput sequencing, we identified differentially expressed miRNAs in sperm, with miR-133a-3p significantly upregulated in samples associated with low FR and available embryo rate (AER). Key regulatory circRNAs and mRNAs were further identified via the Starbase database, intersected with differentially expressed RNA, and analyzed through GO, KEGG, and PPI analyses. The circMYH9/miR-133a-3p/CXCR4 axis emerged as a critical regulatory network. In vitro assays using the GC-2 spd mouse spermatogenic cell line revealed that miR-133a-3p inhibited cell growth and proliferation while promoting apoptosis. circMYH9, acting as a competing endogenous RNA (ceRNA) for miR-133a-3p, modulated CXCR4 expression, enhancing GC-2 spd cell growth and inhibiting apoptosis through the miR-133a-3p/CXCR4 axis. In vivo experiments using a mouse model confirmed that circMYH9 overexpression increased IVF success rates and promoted embryo development via this axis. Mechanistically, miR-133a-3p suppresses sperm fertilization and embryo development by targeting the circMYH9/miR-133a-3p/CXCR4 axis. These findings suggest that this regulatory network could serve as a novel biomarker for assessing fertilization potential and embryo quality in clinical settings and as a potential therapeutic target to improve IVF outcomes and address infertility. This study provides valuable insights into the molecular mechanisms governing sperm function and early embryonic development.

In epithelial ovarian cancer (EOC), platinum resistance, potentially mediated by cancer stem cells (CSCs), often leads to relapse and treatment failure. Here, the role of spindle pole body component 25 (SPC25) as a key determinant promoting stemness and platinum resistance in EOC cells, with its expression being correlated with adverse clinical outcomes is delineated. Mechanistically, SPC25 acts as a scaffolding platform, orchestrating the assembly of an SPC25/RIOK1/MYH9 trimeric complex, triggering RIOK1-mediated phosphorylation of MYH9 at Ser1943. This prompts MYH9 to disengage from the cytoskeleton, augmenting its nuclear accumulation, thus potentiating CTNNB1 transcription and subsequent activation of Wnt/β-catenin signaling. CBP1, a competitive inhibitory peptide, can disrupt the formation of the aforementioned trimeric complex, diminishing the activity of the SPC25/RIOK1/MYH9 axis-mediated Wnt/β-catenin signaling, and thus attenuate CSC phenotypes, thereby enhancing platinum efficacy in vitro, in vivo, and in patient-derived organoids. Therefore, targeting the SPC25/RIOK1/MYH9 axis, which mediates the maintenance of stemness and platinum resistance in EOC cells, may enhance platinum sensitivity and increase survival in patients with EOC.

Breast cancer is one of the most prevalent and diverse malignancies, and, with global cases increasing, the need for biomarkers to inform individual sensitivity to chemotherapeutics has never been greater. Our retrospective clinical analysis predicted that the expression of the fragile site-associated tumor suppressor (FATS) gene was associated with the sensitivity of breast cancer to neoadjuvant chemotherapy with paclitaxel. In vitro experiments subsequently demonstrated that FATS significantly increased the inhibitory effects of paclitaxel on breast cancer cells' migration, growth, and survival. An interaction screen revealed that FATS interacted with MYH9 and promoted its degradation via the ubiquitin-proteasome pathway, thereby downregulating Wnt signaling. By overexpressing FATS and MYH9, we demonstrated that FATS enhanced paclitaxel-induced apoptosis in breast cancer cells by degrading MYH9 to downregulate the Wnt pathway. We also demonstrated in a mouse xenograft model that FATS significantly increased the chemosensitivity of breast cancer cells to paclitaxel in vivo. This study presents a new mechanism by which FATS interacts with MYH9 to suppress the Wnt/β-catenin signaling pathway and induce apoptosis, thus enhancing the sensitivity of breast cancer cells to paclitaxel chemotherapy. The results also propose novel biomarkers for predicting breast cancer sensitivity to neoadjuvant chemotherapy with paclitaxel. Finally, we provide in vivo evidence that the combination of paclitaxel with IWR-1, a novel Wnt pathway inhibitor, synergistically suppresses breast cancer growth, laying the foundation for future trials with this drug combination. These results therefore provide a number of potential solutions for more precise treatment of patients with breast cancer in the future.

Hepatocellular carcinoma (HCC) is a heterogeneous disease with high recurrence and mortality. It is well known that a large proportion of HCCs are caused by hepatitis B virus (HBV) infection. In particular, the HBV X protein (HBX), a multifunctional molecule produced by the virus, plays a leading role in hepatocarcinogenesis. However, the molecular mechanisms underlying HBX-mediated HCC remain not fully elucidated. Recently, liver cancer stem cells (LCSCs), a unique heterogeneous subpopulation of the malignancy, have received particular attention owing to their close association with tumorigenesis. Especially, the modulation of LCSCs by HBX by upregulating CD133, CD44, EpCAM, and CD90 plays a significant role in HBV-related HCC development. More importantly, not only multiple signaling pathways, including Wnt/β-catenin signaling, transforming growth factor-β (TGF-β) signaling, phosphatidylinositol-3-kinase (PI-3 K)/AKT signaling, and STAT3 signaling pathways, but also epigenetic regulation, such as DNA and histone methylation, and noncoding RNAs, including lncRNA and microRNA, are discovered to participate in regulating LCSCs mediated by HBX. Here, we summarized the mechanisms underlying different signaling pathways and epigenetic alterations that contribute to the modulation of HBX-induced LCSCs to facilitate hepatocarcinogenesis. Because LCSCs are important in hepatic carcinogenesis, understanding the regulatory factors controlled by HBX might open new avenues for HBV-associated liver cancer treatment.

Hepatitis B virus is one of the leading causes behind the neoplastic transformation of liver tissue and associated mortality. Despite the availability of many therapies and vaccines, the pathogenic landscape of the virus remains elusive; urging the development of novel strategies based on the fundamental infectious and transformative modalities of the virus-host interactome. Ubiquitination is a widely observed post-translational modification of several proteins, which either regulates the proteins' turnover or impacts their functionalities. In recent years, ample amount of literature has accumulated regarding the ubiquitination dynamics of the HBV proteins as well as the host proteins during HBV infection and carcinogenesis; with direct and detailed characterization of the involvement of HBV in these processes. Interestingly, while many of these ubiquitination events restrict HBV life cycle and carcinogenesis, several others promote the emergence of hepatocarcinoma by putting the virus in an advantageous position. This review sums up the snowballing literature on ubiquitination-mediated regulation of the host-HBV crosstalk, with special emphasis on its influence on the establishment and progression of hepatocellular carcinoma on a molecular level. With the advent of cutting-edge ubiquitination-targeted therapeutic approaches, the findings emanating from this review may potentiate the identification of novel anti-HBV targets for the formulation of novel anticancer strategies to control the HBV-induced hepato-carcinogenic process on a global scale.

The onset of drug resistance in advanced cancer patients markedly diminishes their prognosis. Recently, disulfidptosis, a novel form of cell death, has been identified, triggered by excessive disulfide formation leading to cell shrinkage and F-actin contraction. Previous studies have identified 15 essential genes (FLNA, FLNB, MYH9, TLN1, ACTB, MYL6, MYH10, CAPZB, DSTN, IQGAP1, ACTN4, PDLIM1, CD2AP, INF2, SLC7A11) associated with disulfidptosis. This study sourced pan-cancer mRNA expression data from Xena to thoroughly evaluate the molecular and clinical characteristics of disulfidptosis-related genes. Through unsupervised clustering, mRNA expression data identified the expression levels of disulfidptosis-related genes and potential clusters related to this form of cell death. Kaplan-Meier survival curves illustrated the correlation between different clusters and overall survival. The findings reveal that high expression of disulfidptosis-related genes is linked to poor survival in liver cancer. The GDSC database was utilized to analyze the relationship between disulfidptosis-related genes and the AUC of 198 drugs. The results demonstrate that 12 disulfidptosis-related genes influence sorafenib resistance, as revealed by the intersection of differential genes related to sorafenib resistance from the GSE109211 dataset. Among them, the MYH9 gene was found to play a crucial role in both. Finally, experimental evidence confirmed that MYH9 mitigates sorafenib resistance in hepatocellular carcinoma through disulfidptosis-like changes. This study identifies disulfidptosis as a promising avenue for enhancing the sensitivity of tumor cells to drugs, offering new therapeutic perspectives for future research on disulfidptosis and drug resistance in cancer patients.

Prognosis biomarkers for endometrial cancer (EC) are in need. Recent evidence demonstrated the critical role of disulfidptosis, a novel cell death modality, in cancer. However, limited studies have developed a disulfidptosis-related gene model for EC. Disulfidptosis prognosis score of EC (disulfidptosis-PSEC) were constructed using disulfidptosis-related differently expression genes with the RNA data of 544 EC patients from The Cancer Genome Atlas (TCGA) dataset. Model was evaluated using time-dependent receiver operating characteristic curve analysis for overall survival (OS) and disease-free survival (DFS), along with the hazard ratio (HR) between risk groups. Then, the cellular and molecular profile for different risk groups were performed, along with drug target inference. Disulfidptosis-PSEC demonstrated outstanding prognostic value for OS and DFS, with 5-year area under curve of 0.71 (95% CI, 0.58-0.75) and 0.69 (95% CI, 0.62-0.76), respectively. Low risk group demonstrated better survival with an HR of 0.38 (95% CI, 0.24-0.59) and 0.46 (95% CI, 0.32-0.66) for OS and DFS, respectively. The model was independent of TCGA subtype. Low risk group were featured with more immune cell infiltration and less gene mutation. Serval drug targets, and the therapeutic value of serotonin receptor among copy number (CN)-low subpopulation, were identified. Disulfidptosis-PSEC was a potential prognosis biomarker for EC with targetable biological process.

Fibrosis is a tissue damage repair response caused by multiple pathogenic factors which could occur in almost every apparatus and leading to the tissue structure damage, physiological abnormality, and even organ failure until death. Up to now, there is still no specific drugs or strategies can effectively block or changeover tissue fibrosis. JNKs, a subset of mitogen-activated protein kinases (MAPK), have been reported that participates in various biological processes, such as genetic expression, DNA damage, and cell activation/proliferation/death pathways. Increasing studies indicated that abnormal regulation of JNK signal pathway has strongly associated with tissue fibrosis.

This review designed to sum up the molecular mechanism progresses in the role of JNK signal pathway in organ fibrosis, hoping to provide a novel therapy strategy to tackle tissue fibrosis.

Recent evidence shows that JNK signaling pathway could modulates inflammation, immunoreaction, oxidative stress and Multiple cell biological functions in organ fibrosis. Therefore, targeting the JNK pathway may be a useful strategy in cure fibrosis.

Hepatitis B virus (HBV) infection remains a significant global health burden. The genetic variation of HBV is complex. HBV can be divided into nine genotypes, which show significant differences in geographical distribution, clinical manifestations, transmission routes and treatment response. In recent years, substantial progress has been made through various research methods in understanding the development, pathogenesis, and antiviral treatment response of clinical disease associated with HBV genetic variants. This progress provides important theoretical support for a deeper understanding of the natural history of HBV infection, virus detection, drug treatment, vaccine development, mother-to-child transmission, and surveillance management. This review summarizes the mechanisms of HBV diversity, discusses methods used to detect viral diversity in current studies, and the impact of viral genome variation during infection on the development of clinical disease.

The liver plays an important role in regulating lipid metabolism in animals. This study investigated the function and mechanism of lncLLM in liver lipid metabolism in hens at the peak of egg production. The effect of lncLLM on intracellular lipid content in LMH cells was evaluated by qPCR, Oil Red O staining, and detection of triglyceride (TG) and cholesterol (TC) content. The interaction between lncLLM and MYH9 was confirmed by RNA purification chromatin fractionation (CHIRP) and RNA immunoprecipitation (RIP) analysis. The results showed that lncLLM increased the intracellular content of TG and TC and promoted the expression of genes related to lipid synthesis. It was further found that lncLLM had a negative regulatory effect on the expression level of MYH9 protein in LMH cells. The intracellular TG and TC content of MYH9 knockdown cells increased, and the expression of genes related to lipid decomposition was significantly reduced. In addition, this study confirmed that the role of lncLLM is at least partly through mediating the ubiquitination of MYH9 protein to accelerate the degradation of MYH9 protein. This discovery provides a new molecular target for improving egg-laying performance in hens and treating fatty liver disease in humans.

Clear cell renal cell carcinoma (ccRCC) is a primary kidney cancer with high aggressive phenotype and extremely poor prognosis. Accumulating evidence suggests that circular RNAs (circRNAs) play pivotal roles in the occurrence and development of various human cancers. However, the expression, clinical significance and regulatory role of circRNAs in ccRCC remain largely unclear. Here we report that circSP3 to be increased in tissues from ccRCC patients and ccRCC cells, and to positively correlate with ccRCC malignant features. Knockdown of circSP3 inhibits proliferation, triggers apoptosis, and reduces migration and invasion in different ccRCC cells in vitro. Correspondingly, circSP3 overexpression Promote ccRCC tumorigenicity in a mouse xenograft model. Mechanistically, circSP3 could bind with the ribosome to initiate the translation process to encodes a novel 461-amino acid peptide referred to as SP3-461aa, which protects the MYH9 protein from proteasomal degradation. SP3-461aa played a pivotal role in mediating the oncogenic effects of circSP3 by interacting with the MYH9 protein and activating the PI3K-Akt signaling pathway. These findings suggested that circSP3 plays an important role in ccRCC development and could be a potential biomarker for the treatment and prognosis of ccRCC.

Deubiquitinating enzymes (DUBs) are pivotal in maintaining cell homeostasis by regulating substrate protein ubiquitination in both healthy and cancer cells. Ubiquitin-specific protease 10 (USP10) belongs to the DUB family. In this study, we investigated the clinical and pathological significance of USP10 and Unc-51-like autophagy activating kinase 1 (ULK1) in osteosarcoma (OS), as well as the mechanism of USP10 action in ULK1-mediated autophagy and disease progression.

The analysis of OS and adjacent normal tissues demonstrated that USP10 and ULK1 were significantly overexpressed in OS, and a positive association between their expression and malignant properties was observed. USP10 knockdown in OS cells reduced ULK1 mRNA and protein expression, whereas USP10 overexpression increased ULK1 mRNA and protein expression. In vitro experiments showed that USP10 induced autophagy, cell proliferation, and invasion by enhancing ULK1 expression in OS cell lines. Furthermore, we found that the regulation of ULK1-mediated autophagy, cell proliferation, and invasion in OS by USP10 was dependent on glycogen synthase kinase 3β (GSK3β) activity. Mechanistically, USP10 promoted ULK1 transcription by interacting with and stabilising GSK3β through deubiquitination, which, in turn, increased the activity of the ULK1 promoter, thereby accelerating OS progression. Using a xenograft mouse model, we showed that Spautin-1, a small-molecule inhibitor targeting USP10, significantly reduced OS development, with its anti-tumour activity significantly enhanced when combined with the chemotherapeutic agent cisplatin.

Collectively, we demonstrated that the USP10-GSK3β-ULK1 axis promoted autophagy, cell proliferation, and invasion in OS. The findings imply that targeting USP10 may offer a promising therapeutic avenue for treating OS.

Heat-shock protein 90 (Hsp90) plays a crucial role in tumorigenesis and tumor progression; however, its mechanism of action in gastric cancer (GC) remains unclear. Here, the role of Hsp90 in GC metabolism is the focus of this research. High expression of Hsp90 in GC tissues can interact with glycolysis, collectively affecting prognosis in clinical samples. Both in vitro and in vivo experiments demonstrate that Hsp90 is able to regulate the migration and stemness properties of GC cells. Metabolic phenotype analyses indicate that Hsp90 influences glycolytic metabolism. Mechanistically, Hsp90 interacts with glycolysis-related enzymes, forming multienzyme complexes to enhance glycolysis efficiency and yield. Additionally, Hsp90 binds to cytoskeleton-related proteins, regulating the regional distribution of glycolytic enzymes at the cell margin and lamellar pseudopods. This effect could lead to a local increase in efficient energy supply from glycolysis, further promoting epithelial-mesenchymal transition (EMT) and metastasis. In summary, Hsp90, through its interaction with metabolic enzymes related to glycolysis, forms multi-enzyme complexes and regulates regional distribution of glycolysis by dynamic cytoskeletal adjustments, thereby promoting the migration and stemness of GC cells. These conclusions also support the potential for a combined targeted approach involving Hsp90, glycolysis, and the cytoskeleton in clinical therapy.

Hepatic stellate cells (HSCs) secrete extracellular matrix for collagen deposition, contributing to liver fibrosis. Ferroptosis is a novel type of programmed cell death induced by iron overload-dependent lipid peroxidation. Regulation of ferroptosis in hepatic stellate cells (HSCs) may have therapeutic potential for liver fibrosis. Here, we found that Maf bZIP transcription factor G (MafG) was upregulated in human and murine liver fibrosis. Interestingly, MafG knockdown increased HSCs ferroptosis, while MafG overexpression conferred resistance of HSCs to ferroptosis. Mechanistically, MafG physically interacted with non-muscle myosin heavy chain IIa (MYH9) to transcriptionally activate lipocalin 2 (LCN2) expression, a known suppressor for ferroptosis. Site-directed mutations of MARE motif blocked the binding of MafG to LCN2 promoter. Re-expression of LCN2 in MafG knockdown HSCs restored resistance to ferroptosis. In bile duct ligation (BDL)-induced mice model, we found that treatment with erastin alleviated murine liver fibrosis by inducing HSC ferroptosis. HSC-specific knowdown MafG based on adeno-associated virus 6 (AAV-6) improved erastin-induced HSC ferroptosis and alleviation of liver fibrosis. Taken together, MafG inhibited HSCs ferroptosis to promote liver fibrosis through transcriptionally activating LCN2 expression. These results suggest that MafG/MYH9-LCN2 signaling pathway could be a novel targets for the treatment of liver fibrosis.

Talin2 is localized to large focal adhesions and is indispensable for traction force generation, invadopodium formation, cell invasion as well as metastasis. Talin2 has a higher affinity toward β-integrin tails than talin1. Moreover, disruption of the talin2-β-integrin interaction inhibits traction force generation, invadopodium formation and cell invasion, indicating that a strong talin2-β-integrin interaction is required for talin2 to fulfill these functions. Nevertheless, the role of talin2 in mediation of these processes remains unknown. Here we show that talin2 binds to the N-terminus of non-muscle myosin IIA (NMIIA) through its F3 subdomain. Moreover, talin2 co-localizes with NMIIA at cell edges as well as at some cytoplasmic spots. Talin2 also co-localizes with cortactin, an invadopodium marker. Furthermore, overexpression of NMIIA promoted the talin2 head binding to the β1-integrin tail, whereas knockdown of NMIIA reduced fibronectin and matrix metalloproteinase secretion as well as inhibited cell attachment on fibronectin-coated substrates. These results suggest that talin2 binds to NMIIA to control the secretion of extracellular matrix proteins and this interaction modulates cell adhesion.

Non-muscle myosin IIA (NM IIA) is a motor protein that belongs to the myosin II family. The myosin heavy chain 9 (MYH9) gene encodes the heavy chain of NM IIA. NM IIA is a hexamer and contains three pairs of peptides, which include the dimer of heavy chains, essential light chains, and regulatory light chains. NM IIA is a part of the actomyosin complex that generates mechanical force and tension to carry out essential cellular functions, including adhesion, cytokinesis, migration, and the maintenance of cell shape and polarity. These functions are regulated via light and heavy chain phosphorylation at different amino acid residues. Apart from physiological functions, NM IIA is also linked to the development of cancer and genetic and neurological disorders. MYH9 gene mutations result in the development of several autosomal dominant disorders, such as May-Hegglin anomaly (MHA) and Epstein syndrome (EPS). Multiple studies have reported NM IIA as a tumor suppressor in melanoma and head and neck squamous cell carcinoma; however, studies also indicate that NM IIA is a critical player in promoting tumorigenesis, chemoradiotherapy resistance, and stemness. The ROCK-NM IIA pathway regulates cellular movement and shape via the control of cytoskeletal dynamics. In addition, the ROCK-NM IIA pathway is dysregulated in various solid tumors and leukemia. Currently, there are very few compounds targeting NM IIA, and most of these compounds are still being studied in preclinical models. This review provides comprehensive evidence highlighting the dual role of NM IIA in multiple cancer types and summarizes the signaling networks involved in tumorigenesis. Furthermore, we also discuss the role of NM IIA as a potential therapeutic target with a focus on the ROCK-NM IIA pathway.

Non-muscle myosin heavy chain IIA (MYH9), a member of the non-muscle myosin II (NM II) family, is widely expressed in cells. The interaction of MYH9 with actin in the cytoplasm can hydrolyze ATP, completing the conversion of chemical energy to mechanical motion. MYH9 participates in various cellular processes, such as cell adhesion, migration, movement, and even signal transduction. Mutations in MYH9 are often associated with autosomal dominant platelet disorders and kidney diseases. Over the past decade, tumor-related research has gradually revealed a close relationship between MYH9 and the occurrence and development of tumors. This article provides a review of the research progress on the role of MYH9 in cancer regulation. We also discussed the anti-cancer effects of MYH9 under special circumstances, as well as its regulation of T cell function. In addition, given the importance of MYH9 as a key hub in oncogenic signal transduction, we summarize the current therapeutic strategies targeting MYH9 as well as the ongoing challenges.

Hypertension is a prominent contributor to vascular injury. Deubiquinatase has been implicated in the regulation of hypertension-induced vascular injury. In the present study we investigated the specific role of deubiquinatase YOD1 in hypertension-induced vascular injury. Vascular endothelial endothelial-mesenchymal transition (EndMT) was induced in male WT and YOD1-/- mice by administration of Ang II (1 μg/kg per minute) via osmotic pump for four weeks. We showed a significantly increased expression of YOD1 in mouse vascular endothelial cells upon Ang II stimulation. Knockout of YOD1 resulted in a notable reduction in EndMT in vascular endothelial cells of Ang II-treated mouse; a similar result was observed in Ang II-treated human umbilical vein endothelial cells (HUVECs). We then conducted LC-MS/MS and co-immunoprecipitation (Co-IP) analyses to verify the binding between YOD1 and EndMT-related proteins, and found that YOD1 directly bound to β-catenin in HUVECs via its ovarian tumor-associated protease (OTU) domain, and histidine at 262 performing deubiquitination to maintain β-catenin protein stability by removing the K48 ubiquitin chain from β-catenin and preventing its proteasome degradation, thereby promoting EndMT of vascular endothelial cells. Oral administration of β-catenin inhibitor MSAB (20 mg/kg, every other day for four weeks) eliminated the protective effect of YOD1 deletion on vascular endothelial injury. In conclusion, we demonstrate a new YOD1-β-catenin axis in regulating Ang II-induced vascular endothelial injury and reveal YOD1 as a deubiquitinating enzyme for β-catenin, suggesting that targeting YOD1 holds promise as a potential therapeutic strategy for treating β-catenin-mediated vascular diseases.