Epithelial-mesenchymal transition (EMT) has been extensively studied for its roles in tumor metastasis, the generation and maintenance of cancer stem cells and treatment resistance. Epithelial mesenchymal plasticity allows cells to switch between various states within the epithelial-mesenchymal spectrum, resulting in a mixed epithelial/mesenchymal phenotypic profile. This plasticity underlies the acquisition of multiple malignant features during cancer progression and poses challenges for EMT in tumors. MicroRNAs (miRNAs) in the microenvironment affect numerous signaling processes through diverse mechanisms, influencing physiological activities. This paper reviews recent advances in EMT, the role of different hybrid states in tumor progression, and the important role of miRNAs in EMT. Furthermore, it explores the relationship between miRNA-based EMT therapies and their implications for clinical practice, discussing how ongoing developments may enhance therapeutic outcomes.

Tenacissoside H(TDH), a natural compound extracted from the dried vine stems of Marsdenia tenacissima (Roxb.) Wight et Arn., is considered to have anti-tumor effects. However, the anti-tumor activity of TDH against ATC remains unknown.

Ferroptosis, a novel form of programmed cell death, presents a promising target for therapeutic intervention, particularly in overcoming drug resistance in anaplastic thyroid carcinoma (ATC). We investigated the inhibitory effects of TDH on ATC cells, elucidating its ferroptosis-inducing mechanism, which to our knowledge has not been explored before.

Our findings indicate that TDH exerts an effect on the survival, proliferation, and migration of ATC cells. The strength of effect is dependent on dosage. Notably, ferroptosis marker proteins (GPX4, xCT, HO-1, TFR) were significantly downregulated following TDH treatment, whereas GPX4 and xCT expressions were partially restored post treatment with ferrostatin-1. Furthermore, in vivo studies confirmed that TDH effectively inhibited tumor growth in xenografted 8505C cells.

TDH could be considered a potential agent against ATC via inducing ferroptosis, providing a novel pharmacological basis for treating ATC.

Gastric cancer (GC) poses a major global health challenge, underscoring the need for advanced diagnostic and therapeutic approaches. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have emerged as pivotal regulators in GC, with their dysregulated expression driving key processes such as tumorigenesis, metastasis, immune evasion, and chemoresistance. The functional diversity of ncRNAs across different GC molecular subtypes highlights their potential as biomarkers for improved subtype classification and patient stratification. Beyond their diagnostic value, ncRNAs demonstrate critical regulatory functions in tumor biology, establishing these RNA molecules as promising targets for therapeutic development. Strategies based on RNA hold considerable promise for addressing critical challenges such as immune escape and drug resistance by modulating key signaling pathways. These approaches can enhance immune responses, reprogram the tumor microenvironment, and reverse resistance mechanisms that compromise treatment efficacy, thereby improving clinical outcomes. Although ncRNAs represent a promising frontier in GC precision medicine, further research is required to fully harness their clinical potential.

Epithelial-mesenchymal transition (EMT) plays an essential role in embryonic development, wound healing, and tumor progression. Partial EMT states have been linked to metastatic dissemination and drug resistance. Several interconnected feedback loops at the RNA and protein levels control the transition between different cellular states. Using a combination of mathematical modeling and experimental analyses in the TGFβ-responsive breast epithelial MCF10A cell model, we identify a central role for the tumor suppressor protein Deleted in Liver Cancer 1 (DLC1) during EMT. By extending a previous model of EMT comprising key transcription factors and microRNAs, our work shows that DLC1 acts as a positive regulator of TGFβ-driven EMT, mainly by promoting SNAIL1 expression. Our model predictions indicate that DLC1 loss impairs EMT progression. Experimental analyses confirm this prediction and reveal the acquisition of a partial EMT phenotype in DLC1-depleted cells. Furthermore, our model results indicate a possible EMT reversion to partial or epithelial states upon DLC1 loss in MCF10A cells induced toward mesenchymal phenotypes. The increased EMT plasticity of cells lacking DLC1 may explain its importance as a tumor suppressor.

Pancreatic cancer is the fourth leading cause of cancer-related deaths. Epithelial-mesenchymal transition (EMT) drives aggressive behaviour and unfavourable outcomes in this disease. The zinc finger E-box-binding homeobox 1 (ZEB1) transcription factor is pivotal in orchestrating EMT, promoting tumor cell mobility, metastasis, and immune evasion through phosphorylation events. However, the precise mechanisms underlying individual phosphorylation sites and their relationship with ZEB1's functions in vivo remain inadequately understood.

We assessed EMT using various techniques, including reverse transcription-quantitative polymerase chain reaction (RT-qPCR), immunoblotting, microscopy, migration, and invasion assays. ZEB1 knockdown was achieved via short hairpin RNA (shRNA), while plasmid transfection facilitated the overexpression of ZEB1, extracellular signal-regulated kinase 1 (ERK1), and extracellular signal-regulated kinase 2 (ERK2). Co-immunoprecipitation and kinase assays were used to examine the interaction between ZEB1 and ERK1/2. PANC-1 and HPAC cells were transplanted in an orthotopic mouse model for in vivo analysis.

Sphingosylphosphorylcholine (SPC) induced EMT in PANC-1 and HPAC cells in a dose- and time-dependent manner through the phosphorylation and nuclear translocation of ZEB1. Notably, ERK2 interacted with ZEB1 and catalysed the phosphorylation of serine 322 (S322) within the ZEB1 molecule. Disrupting S322 phosphorylation hindered ZEB1's nuclear translocation, leading to reduced programmed death-ligand 1 (PD-L1) expression and suppressed migration and invasion of pancreatic cancer cells. Furthermore, in an orthotopic mouse model, implantation of S322 phosphorylation-deficient (shZEB1/S322A) pancreatic cancer cells suppressed tumour formation and metastasis. We developed a phosphoS322 detection antibody, which validated ZEB1 phosphorylation in pancreatic cancer cells and tissue samples from patients with pancreatic cancer.

SPC induces ZEB1 phosphorylation, with ERK2, rather than ERK1, targeting the S322 site. Inhibiting S322 phosphorylation mitigates EMT, PD-L1 expression, and progression of pancreatic cancer. The phosphoS322 detection antibody might be a valuable tool for predicting pancreatic cancer prognosis. These findings implicate ERK2 as a potential therapeutic target for pancreatic cancer and highlight phosphoZEB1 as a valuable prognostic marker.

We assessed the correlation between Multicellular tumor spheroids (MCTS) morphology and the oncological profile of lung cancer cells. MCTS were generated in five lung cancer cell lines and classified into Type-A MCTS, which showed strong aggregation, and Type-B MCTS, which showed weak aggregation. Drug resistance was higher in Type-A MCTS, and invasive ability was higher in Type-B MCTS. The oncologic profile of lung cancer cell lines correlated with MCTS morphology. MCTS morphology could thus be used in basic oncology research and as a clinical prognostic tool.Registry and the Registration No. of the study/trial Not Applicable.

Delta-like 3 (DLL3) is an oncogenic protein aberrantly expressed in several tumors, particularly in small-cell lung cancer. DLL3-targeted therapies have recently made significant progress, demonstrating promising preclinical and clinical efficacy. This review aims to explore the mechanisms, challenges, and future opportunities associated with therapies targeting DLL3 for cancer treatment. The biological characteristics of DLL3 and its role in the Notch signaling pathway are introduced first, delving into the role of DLL3 in tumorigenesis and cancer progression. Next, current therapeutic approaches targeting DLL3 are described, including antibody-drug conjugates, T cell engagers, chimeric antigen receptor T cells, and radiopharmaceutical therapy, highlighting their effectiveness and safety in clinical trials. Despite the promising prospects, difficulties remain in the use of DLL3 as a therapeutic target due to tumor heterogeneity, the development of resistance, potential adverse effects, and barriers to patient stratification. Therefore, the potential of combination therapies, the use of innovative drug delivery systems, and ongoing clinical trial advancements are also discussed. Finally, the potential of DLL3-targeted therapies is summarized, highlighting the importance of multidisciplinary research to guide the clinical application and optimization of this emerging treatment strategy. These approaches might provide new therapeutic options, potentially starting a new era in cancer treatment.

Gliomas exhibit suboptimal responses to conventional treatments, with tumor cell migration remaining a significant challenge in therapy. Epithelial-mesenchymal transition (EMT) is crucial for glioma cell invasion, and transforming growth factor β1(TGF-β1) is a key factor promoting proliferation, migration, and EMT in glioblastoma (GBM). Although magnetic fields are widely used in the diagnosis and treatment of various diseases, their effects on EMT in glioma cells remain unclear. In this study, we investigated whether a static magnetic field (SMF) could inhibit EMT and metastasis in glioma cells. Cellular functional assays using the U251 and U87 glioma cell lines were performed to investigate their functional and phenotypic changes. Results showed that TGF-β1 treatment increased the invasion and migration capabilities of glioma cells, while simultaneously reducing apoptosis. However, when SMF was combined with TGF-β1 treatment, a significant reduction in cell migration and invasion was observed, along with an increase in apoptosis. Additionally, this combination treatment significantly decreased the protein expression of mesenchymal markers N-cadherin and β-catenin, as well as reduced the levels of the matrix metalloproteinase (MMP)-2. Collectively, these findings suggest that SMFs may attenuate glioma cell metastasis by inhibiting EMT. Therefore, SMFs could represent a promising therapeutic strategy for diminishing glioma metastasis.

Despite significant progress in characterizing the omics landscape of head and neck squamous cell carcinoma (HNSCC), the development of precision therapies remains limited. One key factor contributing to this challenge is the marked molecular heterogeneity of HNSCC. Further investigation of molecular profiles within HNSCC may facilitate the improvement in more effective precision treatments. Here, we focus on the dysregulation of PDZ and LIM domain protein 3 (PDLIM3) in HNSCC. The expression levels of PDLIM3 were analyzed using public datasets to assess its potential role in tumor progression. We found that PDLIM3 was downregulated in pan-cancer and HNSCC. The prognostic significance of PDLIM3 was evaluated through tissue microarray, and the downregulation of PDLIM3 was correlated with poor HNSCC prognosis. Investigating the implications of PDLIM3 for tumor metastatic ability in vitro, we found that PDLIM3 suppressed the migration and invasion of HNSCC, accompanied by partially impeding the process of epithelial-mesenchymal transition (EMT). Furthermore, PDLIM3 inhibited the transcriptional activity of Yes-associated protein (YAP), suggesting that YAP may be involved in the PDLIM3-mediated suppression of HNSCC metastatic ability. Our findings identify a potential signaling axis wherein PDLIM3 regulates YAP-EMT, thereby influencing tumor metastatic ability, and suggest the potential role of PDLIM3 as a tumor suppressor and prognostic biomarker for HNSCC.

Inflammation is an essential component of the immune response that protects the host against pathogens and facilitates tissue repair. Chronic inflammation is a critical factor in cancer development and progression. It affects every stage of tumor development, from initiation and promotion to invasion and metastasis. Tumors often create an inflammatory microenvironment that induces angiogenesis, immune suppression, and malignant growth. Immune cells within the tumor microenvironment interact actively with cancer cells, which drives progression through complex molecular mechanisms. Chronic inflammation is triggered by factors such as infections, obesity, and environmental toxins and is strongly linked to increased cancer risk. However, acute inflammatory responses can sometimes boost antitumor immunity; thus, inflammation presents both challenges and opportunities for therapeutic intervention. This review examines how inflammation contributes to tumor biology, emphasizing its dual role as a critical factor in tumorigenesis and as a potential therapeutic target.

Triple-negative breast cancer (TNBC) presents a formidable global health challenge, marked by its aggressive behavior and significant treatment resistance. This subtype, devoid of estrogen, progesterone, and HER2 receptors, largely relies on breast cancer stem cells (BCSCs) for its progression, metastasis, and recurrence. BCSCs, characterized by their self-renewal capacity and resistance to conventional therapies, exploit key surface markers and critical signaling pathways like Wnt, Hedgehog, Notch, TGF-β, PI3K/AKT/mTOR and Hippo-YAP/TAZ to thrive. Their adaptability is underscored by mechanisms including drug efflux and enhanced DNA repair, contributing to poor prognosis and high recurrence rates. The tumor microenvironment (TME) further facilitates BCSC survival through complex interactions with stromal and immune cells. Emerging therapeutic strategies targeting BCSCs - ranging from immunotherapy and nanoparticle-based drug delivery systems to gene-editing technologies - aim to disrupt these resistant cells. Additionally, innovative approaches focusing on exosome-mediated signaling and metabolic reprogramming show promise in overcoming chemoresistance. By elucidating the distinct characteristics of BCSCs and their role in TNBC, researchers are paving the way for novel treatments that may effectively eradicate these resilient cells, mitigate metastasis, and ultimately improve patient outcomes. This review highlights the urgent need for targeted strategies that address the unique biology of BCSCs in the pursuit of more effective therapeutic interventions for TNBC.

Opsin3 (OPN3) belongs to the guanine nucleotide-binding protein-coupled receptor superfamily, implicated in several pathological mechanisms that contribute to tumor development and resistance to treatment. This study examined OPN3 expression in triple-negative breast cancer (TNBC) tissues and its function in TNBC cell propagation, invasion, and migration.

The study analyzed OPN3 expression in TNBC patients and its diagnostic value using immunohistochemistry (IHC) staining and The Cancer Genome Atlas (TCGA) data. To evaluate the impact of OPN3 on the growth, invasion, and migration of TNBC cells, both in vitro and in vivo experiments were carried out. The biological mechanisms of OPN3-induced cell migration and invasion were evaluated via quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting (WB) analyses.

In this study, OPN3 upregulation in TNBC tissues was found to be correlated with decreased overall survival (OS) and progression-free survival (PFS) rates. The propagation, invasion, and migration of BT-549 cells were promoted and apoptosis was reduced after OPN3 overexpression. It was silenced in BT-549 cells, which resulted in the opposite effects. Further, the transforming growth factor-beta (TGF-β)/SMAD2 signaling pathway was stimulated and the epithelial-mesenchymal transition (EMT) was modulated by OPN3 overexpression in BT-549 cells.

The findings revealed that OPN3 is involved in the stimulation of the TGF-β/SMAD2 signaling pathway, which promotes the growth, migration, and dissemination of TNBC cells. Moreover, OPN3 can serve as a diagnostic biomarker and a treatment target for TNBC.

Mitochondria play a central, multifunctional role in cancer progression. However, the mechanism of mitochondrial genes in epithelial ovarian cancer (EOC) remains unclear. This study aimed to screen candidate mitochondrial genes in EOC and then to investigate their biological functions and potential mechanisms.

We downloaded Gene Expression Omnibus RNA-seq profiles and identified mitochondrial differentially expressed genes in EOC by bioinformatics analysis. Transcription factor A, mitochondrial (TFAM) expression in EOC tissues was determined by immunohistochemistry. In vitro assays were applied to clarify TFAM function in EOC.

The bioinformatics analysis results showed that the mitochondrial genes TFAM, HSPE1, and CYC1 were significantly upregulated (P < 0.05) in EOC, and their upregulation was associated with a poor prognosis. TFAM was highly expressed in EOC tissues and significantly associated with clinical stage (P = 0.004), lymph node metastasis (P = 0.043), and overall survival (P < 0.05). Silencing TFAM in EOC cells significantly inhibited cell proliferation and migration and induced cell apoptosis (P < 0.05).

TFAM promotes EOC cell secretion of VEGF-A, VEGF-C, VEGF-D, lymphangiogenesis, and EOC lymph node metastasis. Our results may provide new insights into the biological functions and potential mechanisms of TFAM in EOC, which might provide new targets for EOC diagnosis and treatment.

Bladder cancer poses significant clinical challenges due to its high metastatic potential and poor prognosis, especially when it progresses to muscle-invasive stages. Here, we show that the m6A reader YTHDC1 is downregulated in muscle-invasive bladder cancer and is negatively correlated with the expression of epithelial‒mesenchymal transition genes. The functional inhibition or depletion of YTHDC1 increased the migration and invasion of urothelial cells. Integrative analysis of multimodal sequencing datasets provided detailed insights into the molecular mechanisms mediating YTHDC1-dependent phenotypes and identified SMAD6 as a key transcript involved in the invasiveness of urothelial carcinoma of the bladder. Notably, SMAD6 mRNA colocalized less with YTHDC1 in tumoral tissues than in paratumoral tissues, indicating disrupted binding during cancer progression. Our findings establish YTHDC1-dependent m6A reading as a critical epitranscriptomic mechanism regulating bladder cancer invasiveness and provide a paradigm for the epitranscriptomic deregulation of cancer-associated networks.

Background: Renal cell carcinoma (RCC) represents the most common form of invasive kidney cancer in adults. Among the components critical to cellular regulation is Phospholipase C Beta 2 (PLCB2), a member of the phospholipase C enzyme family. This enzyme plays a vital role in managing key cellular functions such as growth, differentiation, migration, and survival. Despite its significant importance, the specific expression patterns and molecular mechanisms of PLCB2 in the progression of RCC are not well understood. Methods: This investigation employed a combination of bioinformatics analyses, scRNA-seq, functional assays, transcriptome sequencing, real-time quantitative PCR (RT-PCR), immunofluorescence, rescue experiments, and Western blotting to explore the regulatory function of PLCB2 in driving the epithelial-mesenchymal transition (EMT) in RCC through the PI3K/AKT signaling pathway. Results:PLCB2 expression is significantly elevated in RCC samples, and this increase is inversely correlated with patient prognosis. The knockdown of PLCB2 in RCC cell lines leads to a marked reduction in cell proliferation, invasion, migration, and EMT. Transcriptome sequencing further revealed that PLCB2 is significantly associated with the PI3K/AKT pathway. Notably, the PI3K activator 740Y-P was able to reverse the reductions in migration, invasion, and EMT caused by the PLCB2 knockdown. Conclusions: Our findings underscore the pivotal role of PLCB2 in regulating RCC invasion and metastasis by modulating the EMT via the PI3K/AKT signaling pathway. This highlights PLCB2 not only as a key prognostic biomarker, but also as a promising therapeutic target in the treatment of advanced-stage RCC, offering new avenues for more effective interventions.

Breast cancer is the most common malignant tumor in the world, and its metastasis is the main cause of death in breast cancer patients. However, the differences between primary breast cancer tissue and lymphatic node, bone, and brain metastases at the single-cell level are not fully understood. We analyzed the microenvironment heterogeneity in samples of primary breast cancer (n = 4), breast cancer lymphatic node metastasis (n = 4), breast cancer brain metastasis (n = 3), and breast cancer bone metastasis (n = 2) using single-cell sequencing data from the GEO database. The malignant epithelial cells were characterized by InferCNV algorithm. The cell-cell communication was analyzed using CellChat package. The biological function of cell subpopulations was analyzed using gene set variation analysis. The expression of STMN1 was analyzed using immunohistochemical staining. The proportion of pCAFs in breast cancer was explored using multispectral immunohistochemical staining. We identified seven cell clusters in primary and metastatic breast cancer (Lymphatic node, brain, and bone metastases) by analyzing single-cell transcriptomic profiles. T-NK and B cells dominated breast cancer with lymphatic node metastasis, whereas fibroblasts were prevalent in brain metastases and primary breast cancer. We identified five T cells (T memory, CD8 + T cells, regulatory T cells, natural killer cells, CD4 + T cells), three B cells (naïve B cells, memory B cells, plasma B cells), and five cancer-associated fibroblasts (CAFs) subpopulations (Smooth muscle cells (SMC), pericyte, antigen-presenting CAFs (apCAFs), proliferative CAFs (pCAFs), and matrix CAFs (mCAFs)). Notably. pCAFs dominated breast cancer with lymphatic node, bone, and brain metastasis. Furthermore, we identified four malignant epithelial cell subpopulations: G0, G1, G2, and G3. The G2 cell population exhibited strong invasion ability, it can differentiate into G3 with strong proliferative ability and proliferation-related G1 cell population after metastasis. Cell-cell communication demonstrated an interaction between pCAFs and metastasis-associated malignant epithelial cells. Finally, we discovered that in advanced breast cancer, the proportion of pCAF increased and was associated with a poor prognosis of breast cancer. This study elucidated the potential cellular origins and drivers of breast cancer metastases to lymphatic nodes, brain, and bone, utilizing single-cell transcriptomic profiles. Furthermore, it demonstrated that increased pCAFs were associated with advanced breast cancer and a poor prognosis.

The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges. A critical process induced by TME signaling is the epithelial-mesenchymal transition (EMT), wherein epithelial cells acquire mesenchymal traits, which enhance their motility and invasiveness and promote metastasis and cancer progression. By targeting various components of the TME, novel investigational strategies aim to disrupt the TME's contribution to the EMT, thereby improving treatment efficacy, addressing therapeutic resistance, and offering a nuanced approach to cancer therapy. This review scrutinizes the key players in the TME and the TME's contribution to the EMT, emphasizing avenues to therapeutically disrupt the interactions between the various TME components. Moreover, the article discusses the TME's implications for resistance mechanisms and highlights the current therapeutic strategies toward TME modulation along with potential caveats.

Triple-negative breast cancer (TNBC) is one of the most difficult subtypes of breast cancer to treat due to its distinct clinical and molecular characteristics. Patients with TNBC face a high recurrence rate, an increased risk of metastasis, and lower overall survival compared to other breast cancer subtypes. Despite advancements in targeted therapies, traditional chemotherapy (primarily using platinum compounds and taxanes) continues to be the standard treatment for TNBC, often with limited long-term efficacy. TNBC tumors are heterogeneous, displaying a diverse mutation profile and considerable chromosomal instability, which complicates therapeutic interventions. The development of chemoresistance in TNBC is frequently associated with the process of epithelial-mesenchymal transition (EMT), during which epithelial tumor cells acquire a mesenchymal-like phenotype. This shift enhances metastatic potential, while simultaneously reducing the effectiveness of standard chemotherapeutics. It has also been suggested that EMT plays a central role in the development of cancer stem cells. Hence, there is growing interest in exploring small-molecule inhibitors that target the EMT process as a future strategy for overcoming resistance and improving outcomes for patients with TNBC. This review focuses on the progression and drug resistance of TNBC with an emphasis on the role of EMT in these processes. We present TNBC-specific and EMT-related molecular features, key EMT protein markers, and various signaling pathways involved. We also discuss other important mechanisms and factors related to chemoresistance in TNBC within the context of EMT, highlighting treatment advancements to improve patients' outcomes.

Cells undergo significant epigenetic and phenotypic change during the epithelial-to-mesenchymal transition (EMT), a process observed in development, wound healing, and cancer metastasis. EMT confers several advantageous characteristics, including enhanced migration and invasion, resistance to cell death, and altered metabolism. In disease, these adaptations could be leveraged as therapeutic targets. Here, we analyze Twist-induced EMT in non-transformed HMLE cells as well as a breast cancer cell line with (MDA-MB-231) and without (MCF7) EMT features to compare differences in metabolic pathways and mitochondrial morphology. Analysis of oxidative and glycolytic metabolism reveals a general EMT-associated glycolytic metabolic phenotype accompanied by increased ATP production. Furthermore, a decrease in mitochondrial size was also associated with EMT-positive cells. However, mitochondrial elongation and spatial dynamics were not consistently altered, as HMLE Twist cells exhibit more rounded and dispersed mitochondria compared to control, while MDA-MB-231 cells exhibit more elongated and clustered mitochondria compared to MCF7 cells. These results provide further insight as to the contextual nature of EMT conferred properties.

Bladder cancer (BLCA) is the tenth most common cancer worldwide, characterized by its high recurrence and progression rates. Thus, identifying prognostic biomarkers and understanding its underlying mechanisms are imperative to enhance patient outcomes. In this study, we aimed to investigate the prognostic significance, expression, functional activity, and underlying mechanisms of RRM2 in BLCA. RRM2 expression and its association with pathological grading and survival were investigated in samples from TCGA dataset and BLCA tissue microarray. CCK8 assays, colony formation assays, wound healing, and transwell assays were performed to assess the role of RRM2 in BLCA cell proliferation and migration. Western blot was employed to investigate alterations in markers associated with epithelial-to-mesenchymal transition (EMT), apoptosis, and cell cycle regulation. Gene set enrichment analysis was performed to investigate the biological processes associated with RRM2, which were subsequently validated. The expression of RRM2 was significantly elevated in both BLCA tissues and cells. Our results also indicated a positive correlation between RRM2 expression and high tumor stage, high tumor grade, and poor survival. Knockdown of RRM2 inhibited cell proliferation and migration of BLCA. RRM2 knockdown significantly induced apoptosis and arrested the cell cycle at the G0/G1 phase. Opposite results were observed in the RRM2 overexpression cells. Additionally, our study demonstrates that RRM2 promotes BLCA progression by activating the PI3K/AKT/mTOR pathway. RRM2 is remarkably correlated with poor prognosis in BLCA and facilitate its progression via PI3K/AKT/mTOR pathway. It is suggested that RRM2 might become an effective prognostic biomarker and potential therapeutic target for BLCA.

Intrabdominal dissemination of malignant mesothelioma (MM) and pseudomyxoma peritonei (PMP) is poorly characterized with respect to the stemness window which malignant cells activate during their reshaping on the epithelial-mesenchymal (E/M) axis. To gain insights into stemness properties and their prognostic significance in these rarer forms of peritoneal metastases (PM), primary tumor cultures from 55 patients selected for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy were analyzed for cancer stem cells (CSC) by aldehyde dehydrogenase 1 (ALDH1) and spheroid formation assays, and for expression of a set of plasticity-related genes to measure E/M transition (EMT) score. Intratumor heterogeneity was also analyzed. Samples from PM of colorectal cancer were included for comparison. Molecular data were confirmed using principal component and cluster analyses. Associations with survival were evaluated using Kaplan-Meier and Cox regression models. The activity of acetylsalicylic acid (ASA), a stemness modifier, was tested in five cultures. Significantly increased amounts of ALDH1bright-cells identified high-grade PMP, and discriminated solid masses from ascitic/mucin-embedded tumor cells in both forms of PM. Epithelial/early hybrid EMT scores and an early hybrid expression pattern correlated with pluripotency factors were significantly associated with early peritoneal progression (p = .0343 and p = .0339, respectively, log-rank test) in multivariable models. ASA impaired spheroid formation and increased cisplatin sensitivity in all five cultures. These data suggest that CSC subpopulations and hybrid E/M states may guide peritoneal spread of MM and PMP. Stemness could be exploited as targetable vulnerability to increase chemosensitivity and improve patient outcomes. Additional research is needed to confirm these preliminary data.

The activation of the human interferon-inducible protein X (IFIX) isoform is associated with maintaining a stable cytoskeleton and inhibiting epithelial-mesenchymal transition (EMT). However, the mechanisms and pathways underlying IFIX-mediated oncogenesis are not well understood. In this study, we investigated the effects of IFIX overexpression and knockdown in CAL-27 and SCC-25 oral squamous cell carcinoma (OSCC) cells. We observed significant variations in the expression of E-cadherin, N-cadherin, vimentin and Snail, as well as changes in wingless/integrated (Wnt) signalling. Our results indicated a strong correlation between IFIX and EMT, as evidenced by quantitative reverse-transcription PCR and Western blotting, which revealed that Wnt3a and Wnt4 pathway components were regulated in IFIX-overexpressing or knockdown cells, with naked cuticle 2 (NKD2) showing the strongest positive correlation. Both IFIX overexpression and knockdown modulated NKD2 expression. NKD2 silencing mimicked the phenotypic effects of IFIX knockdown, inhibiting E-cadherin expression and increasing N-cadherin, Snail and vimentin expression. Additionally, silencing NKD2 restored the anticarcinogenic phenotype associated with IFIX overexpression, affecting cell proliferation, invasion and migration. These findings provide mechanistic insights into the antioncogenic effects of IFIX in OSCC, involving the inhibition of Wnt signalling through NKD2, which leads to cancer-inhibiting phenotypic effects, including restricted EMT.

Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer, characterized by a high incidence in late stages, high mortality rate, and poor prognosis. Src Homology 2 Domain Containing Protein 5 (SH2D5) is a mammalian-specific, uncharacterized scaffolding protein, and its role in LUAD remains unclear. In the present study, we investigated the function and potential mechanisms of SH2D5 in the progression of LUAD. We found aberrant expression of SH2D5 in LUAD tissues and cells, and its high expression is closely associated with poor prognosis in LUAD patients. Through loss-of-function and gain-of-function experiments, we revealed that overexpression of SH2D5 promotes the proliferation and migration abilities of lung adenocarcinoma cells. Gene set enrichment analysis (GSEA) revealed that SH2D5 positively regulates the epithelial-mesenchymal transition (EMT) process in lung adenocarcinoma cells. Additionally, we found that regulating the expression of SH2D5 influenced the phosphorylation levels of AKT, and the rescue experiments with AKT pathway activators/inhibitors partially reversed the tumor progression and EMT processes induced by SH2D5. In summary, our study demonstrated that SH2D5 promotes the migration and EMT process of LUAD cells through the AKT signaling pathway, suggesting that SH2D5 may serve as a crucial potential target for the treatment of metastatic LUAD.

Recurrence and metastasis stand as the primary contributors to mortality among patients with triple-negative breast cancer post-surgery, presenting a formidable clinical obstacle. Chemodynamic therapy (CDT), leveraging metal-ion-mediated Fenton-like reactions within the tumor microenvironment (TME), emerges as a promising avenue for addressing cancer metastasis. Despite recent progress, challenges such as tumor cell antioxidant defenses and epithelial-mesenchymal transition (EMT) impede the efficacy of CDT. Here, we introduce a novel approach using DNA-templated nanosheets (Dz-MnO2) that combine the functions of Mn2+-mediated CDT and DNAzyme-mediated gene therapy to suppress tumor growth and metastasis. The Dz-MnO2 nanosheets respond effectively to the TME, releasing Mn2+ and DNAzyme. The DNAzyme exhibits mRNA cleavage activity, specifically targeting oncogenic transcripts to reduce tumor progression. Mn2+ not only facilitates a Fenton-like reaction, enhancing the chemodynamic treatment effect, but also serves as a cofactor for DNAzyme, improving its catalytic efficiency. Concurrently, the nanosheets robustly silence the Twist1 gene, mitigating the EMT process and reinforcing CDT efficacy by suppressing apoptosis resistance. Results indicate that Dz-MnO2 nanosheets efficiently polarize M2-tumor-associated macrophages (TAMs) into M1-TAMs by locally mitigating tumor hypoxia via catalyzing the decomposition of H2O2 into O2. This collaborative strategy presents a promising approach to enhance CDT, effectively inhibiting tumor recurrence and metastasis.

Epithelial-mesenchymal transition (EMT) plays a crucial role in the migration and invasion capabilities of glioblastoma (GBM) cells. Several studies have established tubulin as a significant regulator of the EMT process. Tubulin beta 2B class IIb (TUBB2B), a critical component of microtubules, has been linked to the prognosis of various tumors. However, the specific biological function and mechanism of TUBB2B in GBM remain unclear.

In vitro experiments demonstrated that TUBB2B knockdown inhibited the migration and invasion of GBM cells, while its overexpression enhanced these capabilities. Western blot, immunofluorescence (IF) and co-immunoprecipitation (Co-IP) assays revealed that TUBB2B interacts with Vimentin. Molecular docking and residue mutation scanning indicated that TUBB2B interacts with Vimentin at the R391/K392/A393/F394 sites. In vivo experiments using nude mice confirmed that TUBB2B knockdown inhibited GBM cell invasion and migration.

TUBB2B was upregulated in GBM tissue samples compared with normal tissues. The sites of TUBB2B(R391/K392/A393/F394) physically interacts with Vimentin to induce EMT, which promotes migration and invasion.

TUBB2B may regulate EMT and promote the migration and invasion of GBM cells through its interaction with Vimentin, highlighting TUBB2B as a potential therapeutic target for GBM.

Papillary thyroid carcinoma (PTC) is the most common malignant tumor of the endocrine system globally. Formononetin (FMNT), an isoflavonoid, exerts anti-tumorigenic effects and chromobox homolog 4 (CBX4) exerts tumor-promoting effect in specific types of tumors. Nevertheless, the predictive values and biological functions of FMNT and CBX4 in the pathological progress of PTC have not been fully understood till now. In the present study, the human PTC cell line TPC-1 was exposed to 0, 10, 30 and 100 µM FMNT for 24 h to elucidate the precise effects of FMNT on the biological behaviors of PTC cells. Moreover, FMNT-treated TPC-1 cells were transfected with oe-CBX4 to evaluate whether CBX4 was implicated in the anticarcinogenic effects of FMNT against PTC. It was demonstrated that FMNT treatment suppressed the proliferation, clone formation, migration, invasion, EMT, angiogenesis and stemness of PTC cells in a dose-dependent manner. Furthermore, it was verified that FMNT targeted CBX4 to downregulate its expression in a dose dependent manner. The suppressive effects of FMNT on the proliferation, clone formation, migration, invasion, EMT, angiogenesis and stemness of PTC cells were partially reversed by CBX4 overexpression. Upregulation of CBX4 abolished the tumor suppression effects of FMNT in the malignant progression of PTC. In conclusion, FMNT might act as a promising anti-tumorigenic agent in PTC, which depends on the downregulation of CBX4.

Cellular plasticity refers to the ability of cells to change their identity or behavior, which can be advantageous in some cases (e.g., tissue regeneration) but detrimental in others (e.g., cancer metastasis). With a better understanding of cellular plasticity, the complexity of cancer cells, their heterogeneity, and their role in metastasis is being unraveled. The plasticity of the cells could also prove as a nemesis to their characterization. In this review, we have attempted to highlight the possibilities and benefits of using multiomics approach in characterizing the plastic nature of cancer cells. There is a need to integrate fragmented evidence at different levels of cellular organization (DNA, RNA, protein, metabolite, epigenetics, etc.) to facilitate the characterization of different forms of plasticity and cell types. We have discussed the role of cellular plasticity in generating intra-tumor heterogeneity. Different omics level evidence is being provided to highlight the variety of molecular determinants discovered using different techniques. Attempts have been made to integrate some of this information to provide a quantitative assessment and scoring of the plastic nature of the cells. However, there is a huge gap in our understanding of mechanisms that lead to the observed heterogeneity. Understanding of these mechanism(s) is necessary for finding targets for early detection and effective therapeutic interventions in metastasis. Targeting cellular plasticity is akin to neutralizing a moving target. Along with the advancements in precision and personalized medicine, these efforts may translate into better clinical outcomes for cancer patients, especially in metastatic stages.

Hepatocellular carcinoma (HCC) is a malignancy characterized by a high fatality rate. Increasing evidence indicating that long non-coding RNAs (lncRNAs) play a regulatory role in hepatocellular carcinoma (HCC). Among them, the correlation between LINC02298 and HCC remains unknown. The expression and subcellular localization of LINC02298 in HCC tissues and cell lines were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Furthermore, the correlation between the expression of LINC02298 and clinicopathological features of HCC patients was analyzed. The regulatory effects of LINC02298 in HCC were investigated using colony formation, cell count Kit-8(CCK8), Transwell, EDU, cell cycle and apoptosis analysis. In addition, the expression of EMT-related proteins were detected by western blotting. Dual-luciferase reporter, RT-qPCR and rescue assays were employed to validate the involvement of the LINC02298/miR-28-5p/CCDC6 axis in the progression of HCC. The up-regulation of LINC02298 was observed in hepatocellular carcinoma (HCC) tissues and cells, and it was found to be correlated with a negative prognosis in patients with HCC. Overexpression of LINC02298 enhanced the proliferation, migration, invasion, and induction of Epithelial-Mesenchymal Transition (EMT) while suppressing apoptosis in HCC cells. LINC02298 bind to miR-28-5p to regulate the expression of CCDC6. Inhibition of miR-28-5p saved the inhibitory effect of shLINC02298, and knockdown of CCDC6 also saved the inhibitory effect of miR-28-5p on HCC in vitro and in vivo. LINC02298 regulates the expression of CCDC6 by sponging of miR-28-5p, thereby facilitating the the malignancy and EMT of HCC.

Invasion and metastasis are the main reasons for the poor prognosis of patients with cervical cancer(CC). SYK is closely related to tumor development. However, the functions of its two isoforms, SYK (L) or SYK (S), are not fully understood to date. In this study, we investigated their biologic functions and possible prognostic values in CC. qRT-PCR was performed to detect the expression of SYK and two variant isoforms in cervical cancer tissues and cells. The association of SYK(L) and SYK(S) with Clinical pathological parameters were evaluated. The migration and invasion was detected by scratch assay and transwell. Western blot was conducted to measure the changes of epithelial mesenchymal transition (EMT)-related markers and PI3K/AKT signaling pathway proteins in cervical cancer cells. LY294002 (inhibitor of PI3K/AKT pathway) and IGF-1 (activator of PI3K/AKT pathway) were applied to evaluate the contribution of PI3K/AKT signaling pathway in cervical cancer cells. The expression of SYK(S) in cervical cancer tissues was significantly higher than that of SYK(L). SYK(L) and SYK(S) were correlated with muscular infiltration, SYK(L) high expression had a better prognosis, whereas SYK(S) high expression predicted a worse disease outcome. Cox multivariate regression analysis demonstrated that SYK(L) expression was an independent prognostic factor. SYK(L) significantly inhibited the proliferation, migration and invasion, while SYK(S) showed the opposite effects. LY294002 blocked SYK (L) knockdown-induced enhancement of migration and invasion as well as the expression EMT-related markers, whereas IGF-1 rescued the decreased migration, invasion and EMT induced by SYK (S) knockdown. The results suggest that SYK(L) and SYK(S) are involved in the progression of cervical cancer through PI3K/AKT signaling pathway, and may serve as potential targets for clinical treatment of advanced cervical cancer.

Renal fibrosis is among the major factors contributing to the development of chronic kidney disease. In this regard, although N6-methyladenosine (m6A) modification and micro-RNAs (miRNAs) have been established to play key roles in diverse physiological processes and disease/disorder development, further research is required to identify the probable mechanisms and processes associated with their involvement in renal fibrosis. In this study, we show that transforming growth factor β1 (TGF-β1)-induced human proximal tubule epithelial cells (HK2) are characterized by dose-dependently higher methyltransferase-like 3 (METTL3) expression. Furthermore, METTL3 was found to enhance pri-miR-199a-3p maturation and miR-199a-3p expression in an m6A-dependent manner, whereas miR-199a-3p sponges prostate apoptotic response 4 (Par4), thereby regulating its expression. Collectively, our findings in this study indicate that the METTL3/miR-199a-3p/Par4 axis plays a key role in the development of obstructive nephrogenic fibrosis.

Gastric cancer (GC) is a malignancy with a relatively high mortality rate. This study aimed to ascertain the prognostic significance of long non-coding RNA (lncRNA) AC010457.1 in GC and elucidate its role in disease progression. The Cancer Genome Atlas (TCGA) database was used to screen the prognosis-associated differentially expressed lncRNAs in GC patients. Kaplan-Meier curves, univariate and multivariate Cox regression analyses were applied to assess the prognostic significance of AC010457.1. In vitro and in vivo functional assays were performed to evaluate the effects of AC010457.1 on cellular proliferation and metastasis. Mechanistic investigations, including Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, Western blotting (WB), Immunofluorescence (IF), and Immunohistochemistry (IHC), were used to explore the signaling pathways activated by AC010457.1. We demonstrated that AC010457.1 was abnormally upregulated in GC tissues, and that this aberrant upregulation was associated with a poor prognosis for GC patients. The functional experiments proved that the downregulated of AC010457.1 hindered GC cell proliferation, migration, and invasive potential. Furthermore, KEGG analysis revealed a significant association between AC010457.1 and the PI3K/AKT signaling pathway, which was further corroborated by WB analysis. Rescue experiments provided additional confirmation that AC010457.1 regulated PI3K/AKT promote GC proliferation, migration, and epithelial-mesenchymal transition (EMT). Collectively, our findings suggest that AC010457.1 overexpression serves as a distinct prognostic risk factor in GC and may represent a promising therapeutic target for the treatment of this malignancy.

Pigmented villonodular synovitis (PVNS) is a rare benign proliferative disease affecting the soft-tissue lining the synovial joints and tendons. Its etiology is poorly understood, largely limiting the availability of current therapeutic options. Here, we mapped the synovial gene and protein profiles of patients with PVNS, revealed a link between synovial inflammation and invasion, and elucidated the potential molecular mechanism involved.

The expression of synovial genes from 6 control individuals, 7 patients with osteoarthritis (OA), and 19 patients with PVNS was analyzed via RNA sequencing. Protein profiles from 5 control individuals, 10 patients with OA, and 32 patients with PVNS were analyzed using label-free proteomics. Microarray and reverse transcription-polymerase chain reaction analyses and immunohistochemical staining were used to evaluate inflammatory cytokine and target gene expression levels in synovial tissue, epithelial cells, and synovial fibroblasts (FLSs) derived from tissue of patients with PVNS. Various signaling pathway inhibitors, small interfering RNAs, and Western blots were used for molecular mechanism studies. Transwell migration and invasion assays were subsequently performed.

In total, 522 differentially expressed proteins were identified in the tissues of patients with PVNS. By integrating RNA sequencing and microarray analyses, significant changes in the expression of epithelial-mesenchymal transition (EMT)-related genes, including transforming growth factor TGF-b induced, neural cadherin, epithelial cadherin, SNAIL, and TWIST, were confirmed in the tissue of patients with PVNS compared to the control tissue. In vitro, TGFβ induced EMT and increased epithelial cell migration and invasion. Moreover, TGFβ not only promoted interactions between epithelial cells and FLSs but also directly increased the migration and invasion abilities of FLSs by activating the classical Smad2/3 and nonclassical JNK/AKT signaling pathways.

This study provides overall protein and gene profiles of PVNS and identifies the crucial role of TGFβ in synovial invasion pathology. Exploring the related molecular mechanism may also reveal a new strategy or target for PVNS therapy.

In this investigation, we explored the molecular dynamics guiding the progression of castration-resistant prostate cancer (CRPC) influenced by Helicobacter pylori (H. pylori)-mediated M2 polarization of macrophages through the IL-17RA/CTSK/EMT axis. An 830-patient clinical trial categorized subjects into hormone-sensitive prostate cancer (HSPC) and CRPC groups. H. pylori infection, evaluated by ELISA, exhibited a higher incidence in CRPC patients, impacting overall survival (OS) and progression-free survival. In-depth in vitro and in vivo experiments, including 16S rDNA sequencing, immunohistochemical tests, and transcriptome analysis, unveiled that H. pylori promotes CRPC growth and metastasis by upregulating IL-17RA and CTSK, leading to enhanced EMT. Notably, M2 macrophages emerged as pivotal immune cells influencing CRPC progression. This study uncovers a novel pathway wherein H. pylori enrichment exacerbates CRPC by inducing macrophage M2 polarization, IL-17RA/CTSK expression, and EMT activation, shedding light on a previously unrecognized mechanism contributing to the growth and metastasis of CRPC.

Ovarian cancer (OC) is one of the cancers with a high incidence at present, which poses a severe threat to women's health. This study focused on identifying the heterogeneity among malignant epithelial cell OC and constructing an effective prognostic signature to predict prognosis and immunotherapy according to a multidisciplinary study.

The InterCNV algorithm was used to identify the heterogeneity of OC based on the scRNA-seq and bulk RNA-seq data. Six algorithms selected EMTscore. An effective prognostic signature was conducted using the COX and Least Absolute Shrinkage and Selection Operator (LASSO) regression algorithms. The texting datasets were used to assess the accuracy of the prognostic signature. We evaluated different immune characteristics and immunotherapy response differences among other risk groups.

A prognostic signature including 14 genes was established. The patients in the high-risk group have poor survival outcomes. We also found that the patients in the low-risk group have higher immune cell infiltration, enrichment of immune checkpoints, and immunotherapy response, suggesting that the patients in the low-risk group may be more sensitive to immunotherapy. Finally, the laboratory test results showed that KREMEN2 was identified as a novel biomarker and therapeutic target for OC patients.

Our study established a GRG signature consisting of 16 genes based on the scRNA-seq and bulk RNA-seq data, which provides a new perspective on the prediction of prognosis and treatment strategy for OC.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy characterised by late diagnosis and poor prognosis. Despite advancements, current diagnostic and prognostic strategies remain limited. Liquid biopsy techniques, including circulating tumour DNA (ctDNA), circulating tumour cells (CTCs), circulating tumour exosomes, and proteomics, offer potential solutions to improve PDAC diagnosis, prognostication, and management. A systematic search of Ovid MEDLINE identified studies published between 2019 and 2024, focusing on liquid biopsy biomarkers for PDAC. A total of 49 articles were included. ctDNA research shows some promise in diagnosing and prognosticating PDAC, especially through detecting mutant KRAS in minimal residual disease assays. CTC analyses had low sensitivity for early-stage PDAC and inconsistent prognostic results across subpopulations. Exosomal studies revealed diverse biomarkers with some diagnostic and prognostic potential. Proteomics, although relatively novel, has demonstrated superior accuracy in PDAC diagnosis, including early detection, and notable prognostic capacity. Proteomics combined with CA19-9 analysis has shown the most promising results to date. An update on multi-cancer early detection testing, given its significance for population screening, is also briefly discussed. Liquid biopsy techniques offer promising avenues for improving PDAC diagnosis, prognostication, and management. In particular, proteomics shows considerable potential, yet further research is needed to validate existing findings and comprehensively explore the proteome using an unbiased approach.

Previous research has revealed that platelets promote tumor metastasis by binding to circulating tumor cells (CTCs). However, the role of platelets in epithelial-mesenchymal transition (EMT) of cancer cells at the primary tumor site, the crucial initial step of tumor metastasis, remains to be elucidated. Here, we found that platelet releasate enhanced EMT and motility of hepatocellular carcinoma (HCC) cells via AMPK/mTOR-induced autophagy. RNA-seq indicated that platelet releasate altered TGF-β signaling pathway of cancer cells. Inhibiting TGFBR or deleting platelet TGF-β1 suppressed AMPK/mTOR pathway activation and autophagy induced by platelet releasate. Compared with Pf4cre-; Tgfb1fl/fl mice, HCC orthotopic models established on Pf4cre+; Tgfb1fl/fl mice showed reduced TGF-β1 in primary tumors, which corresponded with decreased cancer cell EMT, autophagy, migration ability and tumor metastasis. Inhibition of autophagy via Atg5 knockdown in cancer cells negated EMT and metastasis induced by platelet-released TGF-β1. Clinically, higher platelet count correlated with increased TGF-β1, LC3 and N-cad expression in primary tumors of HCC patients, suggesting a link between platelets and HCC progression. Our study indicates that platelets promote cancer cell EMT in the primary tumor and HCC metastasis through TGF-β1-induced HCC cell autophagy via the AMPK/mTOR pathway. These findings offer novel insights into the role of platelets in HCC metastasis and the potential therapeutic targets for HCC metastasis.