Epithelial-mesenchymal transition (EMT) is a cellular de-differentiation process that provides cells with the increased plasticity and stem cell-like traits required during embryonic development, tissue remodeling, wound healing and metastasis. Morphologically, EMT confers tumor cells with fibroblast-like properties that lead to the rearrangement of cytoskeleton (loss of stiffness) and decrease of membrane rigidity by incorporating high level of poly-unsaturated fatty acids (PUFA) in their phospholipid membrane. Although large amounts of PUFA in membrane reduces rigidity and offers capabilities for tumor cells with the unbridled ability to stretch, bend and twist in metastasis, these PUFA are highly susceptible to lipid peroxidation, which leads to the breakdown of membrane integrity and, ultimately results in ferroptosis. To escape the ferroptotic risk, EMT also triggers the rewiring of metabolic program, particularly in lipid metabolism, to enforce the epigenetic regulation of EMT and mitigate the potential damages from ferroptosis. Thus, the interplay among EMT, lipid metabolism, and ferroptosis highlights a new layer of intricated regulation in cancer biology and metastasis. Here we summarize the latest findings and discuss these mutual interactions. Finally, we provide perspectives of how these interplays contribute to cellular plasticity and ferroptosis resistance in metastatic tumor cells that can be explored for innovative therapeutic interventions.

Lysyl oxidase-like-1 (LOXL1) is a copper-dependent amine oxidase that maintains the structural integrity of the extracellular matrix (ECM) by catalyzing the cross-linking of collagen and elastin. However, aberrations in LOXL1 expression can contribute to diseases like glaucoma, tissue fibrosis, and cancer. LOXL1 has been found to be overexpressed in various malignancies, playing a pivotal role in tumor growth and metastasis. Although some studies suggest tumor-suppressive attributes of LOXL1, its role in tumorigenesis remains controversial. Research on LOXL1 has been primarily focused on pseudoexfoliation syndrome/glaucoma, with limited reviews on its impact on cancer. This review aims to explore LOXL1 comprehensively, including its structure, biological effects, and regulatory processes. Emphasis is placed on understanding the relationship between LOXL1 and tumorigenesis, specifically how LOXL1 influences tumor microenvironment remodeling, tumorigenesis, and metastasis. The review also discusses potential therapeutic strategies targeting LOXL1 for anti-fibrosis and anti-tumor interventions.

The process of epithelial-mesenchymal transition (EMT) is crucial in various physiological/pathological circumstances such as development, wound healing, stem cell behavior, and cancer progression. It involves the conversion of epithelial cells into a mesenchymal phenotype, which causes the cells to become highly motile. This reprogramming is initiated and controlled by various signaling pathways and governed by several key transcription factors, including Snail 1, Snail 2 (Slug), TWIST 1, TWIST2, ZEB1, ZEB2, PRRX1, GOOSECOID, E47, FOXC2, SOX4, SOX9, HAND1, and HAND2. The intracellular signaling pathways are activated/inactivated by signals received from the extracellular environment and the transcription factors are carefully regulated at the transcriptional, translational, and post-translational levels to maintain tight regulatory control of EMT. One of the most important pathways involved in this process is the transforming growth factor-β (TGFβ) family signaling pathway. This review will discuss the role of EMT in promoting epithelial cancer progression and the convergence/interplay of multiple signaling pathways and transcription factors that regulate this phenomenon.

The initiation and progression of clear cell renal cell carcinoma (ccRCC) are closely linked to significant metabolic alterations. Specifically, lipid metabolism alterations and their association with the high invasiveness in ccRCC require further investigation. After conducting RNA-sequencing (RNA-seq), we discovered that Hydroxyacyl-CoA Dehydrogenase Trifunctional Multienzyme Complex Subunit Beta (HADHB) was significantly downregulated in the highly invasive ccRCC cell line. It was found that the expression of HADHB in ccRCC tumor tissues was lower than that in paracancer tissues, which is associated with poor patient prognosis. Subsequently, we confirmed that highly invasive ccRCC exhibited an increased lipid accumulation due to the suppression of mitochondrial fatty acid transport and enhanced conversion of fatty acids to triglycerides within cancer cells. Specifically, the downregulation of HADHB inhibited mitochondrial fatty acid β-oxidation (FAO) in cancer cells, leading to partial impairment of mitochondrial function and decreased ATP production. However, this trade-off involving the reduction of a high-yield ATP production conferred an advantage by reducing reactive oxygen species (ROS) generation within cancer cells, thereby protecting them from oxidative stress and enhancing their invasive potential. Furthermore, the downregulation of HADHB promoted epithelial-mesenchymal transition (EMT) and angiogenesis in cancer cells, accelerating the progression of ccRCC and endowing ccRCC cells with metastatic capabilities.

Ovarian cancer (OC), a highly lethal gynaecological malignancy, is often diagnosed at advanced stages, resulting in a poor prognosis. Sialylation, an important form of glycosylation, significantly contributes to the progression of various solid tumours, including OC. Aberrant sialylation promotes tumour progression and metastasis by altering the structure and function of glycoproteins. Although its role in several solid tumours is well documented, the role of abnormal sialylation in OC and its potential as a therapeutic target remain poorly understood. This review highlights sialylation as a key regulator of the progression, metastasis, and drug resistance of OC. A deeper understanding of altered sialylation can contribute to the identification of novel therapeutic strategies for OC.

Epithelial-mesenchymal transition (EMT) plays critical roles in tumor progress and treatment resistance of ovarian cancer (OC), resulting in the most deadly gynecological cancer in women. However, the cell-intrinsic mechanism underlying EMT in OC remains less illuminated.

SKOV3, the OC cell line, was treated with TGF-β to induce EMT or with SB431542, an inhibitor of the TGF-β signaling pathway, to reduce migration. The function of HBO1 in EMT was confirmed by knock-down or overexpression of HBO1 in SKOV3 cells. The role of HBO1 in cell proliferation and apoptosis of SKOV3 cells was analyzed by flow cytometry. The whole-genome transcriptome was used to compare significantly different genes in control and HBO1-KD SKOV3 cells. T-cell cytotoxicity assays were measured by an IVIS spectrum. The chromatin binding of HBO1 was investigated using CUT&Tag-seq.

Here, we show that HBO1, a MYST histone acetyltransferase (HAT), is a cell-intrinsic determinant for EMT in OC cells. HBO1 is greatly elevated during TGF-β-triggered EMT in SKOV3 OC cells as well as in later stages of clinical OC samples. HBO1 Knock-down (KD) in SKOV3 cells blocks TGF-β-triggered EMT, migration, invasion and tumor formation in vivo. Interestingly, HBO1 KD in SKOV3 cells suppresses their resistance to CAR-T cells. Mechanistically, HBO1 co-binds the gene sets responsible for EMT with SMAD4 and orchestrates a gene regulatory network critical for tumor progression in SKOV3 cells.

HBO1 plays an essential onco-factor to drive EMT and promote the immunotherapy resistance in ovarian cancer cells. Together, we reveal a critical role of HBO1 mediated epigenetic mechanism in OC progression, providing an insight into designing new therapy strategies.

Epithelial-mesenchymal transition (EMT) is a process in which epithelial cells, defined by apical-basal polarity and tight intercellular junctions, acquire migratory and invasive properties characteristic of mesenchymal cells. Under normal conditions, EMT directs essential morphogenetic events in embryogenesis and supports tissue repair. When dysregulated, EMT contributes to pathological processes such as organ fibrosis, chronic inflammation, and cancer progression and metastasis. Matrix metalloproteinases (MMPs)-a family of zinc-dependent proteases that degrade structural components of the extracellular matrix-sit at the nexus of this transition by dismantling basement membranes, activating pro-EMT signaling pathways, and cleaving adhesion molecules. When normally regulated, MMPs promote balanced ECM turnover and support the cyclical remodeling necessary for proper development, wound healing, and tissue homeostasis. When abnormally regulated, MMPs drive excessive ECM turnover, thereby promoting EMT-related pathologies, including tumor progression and fibrotic disease. This review provides an integrated overview of the molecular mechanisms by which MMPs both initiate and sustain EMT under physiological and disease conditions. It discusses how MMPs can potentiate EMT through TGF-β and Wnt/β-catenin signaling, disrupt cell-cell junction proteins, and potentiate the action of hypoxia-inducible factors in the tumor microenvironment. It discusses how these pathologic processes remodel tissues during fibrosis, and fuel cancer cell invasion, metastasis, and resistance to therapy. Finally, the review explores emerging therapeutic strategies that selectively target MMPs and EMT, ranging from CRISPR/Cas-mediated interventions to engineered tissue inhibitors of metalloproteinases (TIMPs), and demonstrates how such approaches may suppress pathological EMT without compromising its indispensable roles in normal biology.

Cellular pliancy refers to the unique disposition of different stages of cellular differentiation to transform when exposed to specific oncogenic insults. This concept highlights a strong interconnection between cellular identity and tumorigenesis, and implies overcoming of epigenetic barriers defining cellular states. Emerging evidence suggests that the cell-type-specific response to intrinsic and extrinsic stresses is modulated by accessibility to certain areas of the genome. Understanding the interplay between epigenetic mechanisms, cellular differentiation, and oncogenic insults is crucial for deciphering the complex nature of tumorigenesis and developing targeted therapies. Hence, cellular pliancy relies on a dynamic cooperation between the cellular identity and the cellular context through epigenetic control, including the reactivation of cellular mechanisms, such as epithelial-to-mesenchymal transition (EMT). Such mechanisms and pathways confer plasticity to the cell allowing it to adapt to a hostile environment in a context of tumor initiation, thus changing its cellular identity. Indeed, growing evidence suggests that cancer is a disease of cell identity crisis, whereby differentiated cells lose their defined identity and gain progenitor characteristics. The loss of cell fate commitment is a central feature of tumorigenesis and appears to be a prerequisite for neoplastic transformation. In this context, EMT-inducing transcription factors (EMT-TFs) cooperate with mitogenic oncoproteins to foster malignant transformation. The aberrant activation of EMT-TFs plays an active role in tumor initiation by alleviating key oncosuppressive mechanisms and by endowing cancer cells with stem cell-like properties, including the ability to self-renew, thus changing the course of tumorigenesis. This highly dynamic phenotypic change occurs concomitantly to major epigenome reorganization, a key component of cell differentiation and cancer cell plasticity regulation. The concept of pliancy was initially proposed to address a fundamental question in cancer biology: why are some cells more likely to become cancerous in response to specific oncogenic events at particular developmental stages? We propose the concept of epipliancy, whereby a difference in epigenetic configuration leads to malignant transformation following an oncogenic insult. Here, we present recent studies furthering our understanding of how the epigenetic landscape may impact the modulation of cellular pliancy during early stages of cancer initiation.

This study examines the critical role of non-coding RNAs (ncRNAs) in regulating epithelial-mesenchymal transition (EMT) in breast cancer, a prevalent malignancy with significant metastatic potential. EMT, wherein cancer cells acquire mesenchymal traits, is fundamental to metastasis. ncRNAs-such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs)-modulate EMT by influencing gene expression and signaling pathways, affecting cancer cell migration and invasion. This review consolidates recent findings on ncRNA-mediated EMT regulation and explores their diagnostic and therapeutic potential. Specifically, miRNAs inhibit EMT-related transcription factors, while lncRNAs and circRNAs regulate gene expression through interactions with miRNAs, impacting EMT progression. Given the influence of ncRNAs on metastasis and therapeutic resistance, advancing ncRNA-based biomarkers and treatments holds promise for improving breast cancer outcomes.

In the domain of addressing cancer resistance, challenges such as limited effectiveness and treatment resistance remain persistent. Hypoxia is a key feature of solid tumors and is strongly associated with poor prognosis in cancer patients. Another significant portion of the development of acquired drug resistance is attributed to tumor stemness. Cancer stem cells (CSCs), a small tumor cell subset with self-renewal and proliferative abilities, are crucial for tumor initiation, metastasis, and intra-tumoral heterogeneity. Studies have shown a significant association between hypoxia and CSCs in the context of tumor resistance. Recent studies reveal a strong link between hypoxia and tumor stemness, which together promote tumor survival and progression during treatment. This review elucidates the interplay between hypoxia and CSCs, as well as their correlation with resistance to therapeutic drugs. Targeting pivotal genes associated with hypoxia and stemness holds promise for the development of novel therapeutics to combat tumor resistance.

Transmembrane protein 52B (TMEM52B) is a novel gene expressed widely in various normal human tissues; however, the biological function of TMEM52B in cancer remains largely unknown. Previously, we demonstrated that TMEM52B is a novel modulator of E-cadherin and EGFR activity, and that it has tumor suppressor-like activity using both experimental and clinical analyses. Here, we hypothesized that the extracellular domain (ECD) of TMEM52B may exert tumor-suppressing activity.

We designed and evaluated the therapeutic potential of TMEM52B ECD-derived peptides in vitro and in vivo. The molecular mechanisms underlying the anti-cancer activity of the peptides were explored.

TMEM52B ECD-derived peptides reduced cancer cell survival, invasion, and anchorage-independent growth, which was accompanied by decreased phosphorylation of ERK1/2 and AKT. The peptides maintained intact E-cadherin at organized cell-cell junctions, leading to reduced β-catenin activity. They also inhibited generation of soluble E-cadherin and activation of EGFR by binding directly to the E-cadherin ECD and interfering with the interaction between soluble E-cadherin and EGFR. Peptides fused to the Fc domain of human IgG1 efficiently inhibited tumor growth in a colon cancer xenograft model and reduced survival of circulating tumor cells in an early metastasis model.

These results strongly suggest that TMEM52B ECD-derived peptides could provide a platform for the development of novel anti-cancer therapeutics and furnish a useful tool for exploring the function of TMEM52B in modulating the interplay between E-cadherin and EGFR.

PARP inhibitors are a class of agents that have shown significant preclinical activity in models defective in homologous recombination (HR). The identification of synthetic lethality between HR defects and PARP inhibition led to several clinical trials in tumors with known HR defects (initially mutations in BRCA1/2 genes and subsequently in other genes involved in HR). These studies demonstrated significant responses in breast and ovarian cancers, which are known to have a significant proportion of patients with HR defects. Since the approval of the first PARP inhibitor (PARPi), olaparib, several other inhibitors have been developed, expanding the armamentarium available to clinicians in this setting. The positive results obtained in breast and ovarian cancer have expanded the use of PARPi in other solid tumors with HR defects, including prostate and pancreatic cancer in which these defects have been identified. The clinical trials have demonstrated responses to PARPi which are now also available for the subset of patients with prostate and pancreatic cancer with HR defects. This review summarizes the results obtained in solid tumors with PARPi and their potential use when combined with other agents, including immune checkpoint inhibitors that are likely to further increase the survival of these patients which still needs a dramatic improvement.

The epithelial-mesenchymal transition (EMT) is a critical process for cancer to metastasize by promoting invasiveness and dissemination of cancer cells in the body. Understanding and tracking EMT could improve cancer therapy by intervening in metastasis. Current approaches for investigating and detecting the EMT process often utilize traditional molecular biology techniques like immunohistochemistry, mass spectrometry and sequencing. These approaches have provided valuable insights into understanding signaling pathways and identifying biomarkers. Liquid biopsy analysis using advanced nanotechnologies allows the longitudinal tracking of EMT in patients to become feasible. This review article offers a molecular overview of EMT, summarizes current EMT models used in cancer research, and reviews both traditional techniques and emerging nanotechnologies employed in recent EMT studies. Additionally, we discuss the limitations and prospects of applying nanotechnologies in EMT research. By evaluating this rapidly emerging field, we propose strategies to facilitate the clinical translation of nanotechnologies for early detection and monitoring of EMT.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, necessitating the development of innovative treatment strategies. Recent research has underscored the significant role of non-coding RNAs (ncRNAs) in CRC pathogenesis, offering new avenues for diagnosis and therapy. In this review, we delve into the intricate roles of various ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), in CRC progression, epithelial-mesenchymal transition (EMT), metastasis, and drug resistance. We highlight the interaction of these ncRNAs with and regulation of key signaling pathways, such as Wnt/β-catenin, Notch, JAK-STAT, EGFR, and TGF-β, and the functional relevance of these interactions in CRC progression. Additionally, the review highlights the emerging applications of nanotechnology in enhancing the delivery and efficacy of ncRNA-based therapeutics, which could address existing challenges related to specificity and side effects. Future research directions, including advanced diagnostic tools, targeted therapeutics, strategies to overcome drug resistance, and the integration of personalized medicine approaches are discussed. Integrating nanotechnology with a deeper understanding of CRC biology offers the potential for more effective, targeted, and personalized strategies, though further research is essential to validate these approaches.

Background: The causal relationship between exposure to ultraviolet radiation and the development of skin cancers requires constant research for possible orchestrating mechanisms. In recent years, the Hippo pathway, along with its effector protein YAP, became implicated in cutaneous carcinogenesis; however, Hippo pathway regulation by ultraviolet radiation has not been described thoroughly. In order to address this issue, we focused on how different doses of ultraviolet B affect Hippo signaling pathway components and its upstream regulators, JNK1/2 and ABL1, in human keratinocytes. Additionally, we decided to determine how silencing of YAP influences Hippo pathway component expression. Methods: Primary epidermal keratinocytes were irradiated using UVB lamps with increasing doses of ultraviolet B radiation (including 311 nm UVB). Real-time PCR was used to determine the mRNA levels of each investigated gene. The experiment was then performed after YAP silencing using siRNA transfection. Additionally, we determined the mRNA expression of Hippo pathway components in an A431 cSCC cell line. Results: We observed that YAP mRNA expression in the A431 cell line was insignificant in comparison to control, while in the case of LATS1/2, a significant increase was noted. UVB irradiation did not change the levels of YAP mRNA expression in human epidermal keratinocytes. LATS1, LATS2, ABL1 and MAP4K4 mRNA expression was significantly upregulated after UVB irradiation in non-YAP-silenced keratinocytes in a dose-dependent manner, while after YAP silencing, only LATS2 and ABL1 showed significant mRNA upregulation. The 311 nm UVB irradiation resulted in significant, dose-dependent mRNA upregulation in non-YAP-silenced keratinocytes for LATS1, ABL1 and MAP4K4. After YAP silencing, a significant change in mRNA expression was present only in the case of ABL1. Conclusions: YAP mRNA expression does not significantly increase after exposure to UVB; however, it upregulates the expression of its proven (LATS1/2, JNK1/2) regulators, suggesting that in real-life settings, UV-induced dysregulation of the Hippo pathway may not be limited to YAP.

Bladder cancer continues to pose a substantial global health challenge, marked by a high mortality rate despite advances in treatment options. Therefore, in-depth understanding of molecular mechanisms related to disease onset, progression, and patient survival is of utmost importance in bladder cancer research. Here, we aimed to investigate the underlying mechanisms using a stringent differential expression and survival analyses-based pipeline.

Gene and miRNA expression data from TCGA and NCBI GEO databases were analyzed. Differentially expressed genes between normal vs tumor, among tumor aggressiveness groups and between early vs advanced stage were identified using Student's t-test and ANOVA. Kaplan-Meier survival analyses were conducted using R. Functional annotation, miRNA target and transcription factor prediction, network construction, random walk analysis and gene set enrichment analyses were performed using DAVID, miRDIP, TransmiR, Cytoscape, Java and GSEA respectively.

We identified elevated endoplasmic reticulum (ER) stress response as key culprit, as an eight-gene unfolded protein response (UPR)-related gene signature (UPR-GS) drives aggressive disease and poor survival in bladder cancer patients. This elevated UPR-GS is linked to the downregulation of two miRNAs from the miR-29 family (miR-29b-2-5p and miR-29c-5p), which can limit UPR-driven tumor aggressiveness and improve patient survival. At further upstream, the inflammation-related NFKB transcription factor inhibits miR-29b/c expression, driving UPR-related tumor progression and determining poor survival in bladder cancer patients.

These findings highlight that the aberrantly activated UPR, regulated by the NFKB-miR-29b/c axis, plays a crucial role in tumor aggressiveness and disease progression in bladder cancer, highlighting potential targets for therapeutic interventions and prognostic markers in bladder cancer management.

Collective cell migration and tissue morphogenesis play a variety of important roles in the development of many species. Tissue morphogenesis often generates mechanical forces that alter cell shapes and arrangements, resembling collective cell migration-like behaviors. Genetic methods have been widely used to study collective cell migration and its like behavior, advancing our understanding of these processes during development. However, a growing body of research shows that collective cell migration during development is not a simple behavior but is often combined with other cellular and tissue processes. In addition, different surrounding environments can also influence migrating cells, further complicating collective cell migration during development. Due to the complexity of developmental processes and tissues, traditional genetic approaches often encounter challenges and limitations. Thus, some methods with spatiotemporal control become urgent in dissecting collective cell migration and tissue morphogenesis during development. Optogenetics is a method that combines optics and genetics, providing a perfect strategy for spatiotemporally controlling corresponding protein activity in subcellular, cellular or tissue levels. In this review, we introduce the basic mechanisms underlying different optogenetic tools. Then, we demonstrate how optogenetic methods have been applied in vivo to dissect collective cell migration and tissue morphogenesis during development. Additionally, we describe some promising optogenetic approaches for advancing this field. Together, this review will guide and facilitate future studies of collective cell migration in vivo and tissue morphogenesis by optogenetics.

Up to 90% of cancer-related fatalities could be attributed to metastasis. Therefore, understanding the mechanisms that facilitate tumor cell metastasis is beneficial for improving patient survival and results. EMT is considered the main process involved in the invasion and spread of CRC. Essential molecular components like Wnt, TGF-β, and PI3K/Akt play a role in controlling EMT in CRC, frequently triggered by various factors such as Snail, Twist, and ZEB1. These factors affect not only the spread of CRC but also determine the reaction to chemotherapy. The influence of non-coding RNAs, especially miRNAs and lncRNAs, on the regulation of EMT is clear in CRC. Exosomes, involved in cell-to-cell communication, can affect the TME and metastasis of CRC. Pharmacological substances and nanoparticles demonstrate promise as efficient modulators of EMT in CRC. Chitosan and HA are two major carbohydrate polymers with considerable potential in inhibiting CRC. Chitosan and HA can be employed to modify nanoparticles to enhance cargo transport for reducing CRC. Additionally, chitosan and HA-modified nanocarriers, which can be utilized as potential approaches in suppressing EMT and reversing drug resistance in CRC, can inhibit EMT and chemoresistance, crucial components in tumorigenesis.

Gastric cancer (GC) is one of the leading causes of cancer-related deaths in humans worldwide. Fibroblast growth factor family (FGFs) and the Hippo signaling pathway play an important role in the epithelial-mesenchymal transition (EMT) process of GC. YAP1, a key mediator of the Hippo pathway, plays an important role in tumor genesis. Alternative splicing of human YAP1 mRNA results in two major isoforms: YAP1-1, which contains a single WW domain, and YAP1-2, which contains two WW domains, respectively. There are significant differences in post-transcriptional regulation and function. Basic FGF (bFGF) treatment promoted the EMT process of most GC cell lines, and the proliferation ability was enhanced. This process may be related to the upregulation of YAP1, the proliferation ability of GC was significantly alleviated upon YAP1 knockdown. bFGF treatment can induce EMT of GC through YAP1-2 and enhance their proliferative ability. In this process, bFGF may enhance the nuclear localization of YAP1-2.In the mouse model of intraperitoneal implantation tumorigenesis, it was shown that under the action of bFGF, the expressing YAP1-2 cell lines could form larger tumors than the expressing YAP1-1, but both of them were larger than the YAP1 knockdown. Our results show that YAP1-2 is the main subtype of bFGF-induced EMT and proliferation of GC cells.

Purinergic ligand-gated ion channel 7 receptor (P2X7R) has essential functions in tumor proliferation, apoptosis, metastasis, and invasion, and the purpose of this study was to explore the effects of P2X7R on the biological behaviors of MCF-7 and MDA-MB-231 cells. A bioinformatics analysis of P2X7R expression in breast cancer was performed and its relationships with overall survival and immune cell infiltration were determined. P2X7R ion channel function was detected via a Fluo-4-AM assay. Proliferation, migration and invasion were investigated using CCK-8, scratch wound healing, and Transwell assays, respectively. The levels of P2X7R, JNK, p-JNK, Akt, p-Akt, E-cadherin, N-cadherin, vimentin and GAPDH were detected by western blotting. The role of P2X7R on the biological behaviors of MCF-7 cells was detected in vivo. Bioinformatics analysis revealed an obvious increase in the expression of P2X7R in breast cancer and differences were observed among the different subtypes. High expression of P2X7R was negatively correlated with overall survival and affected immune cell infiltration. The experimental results revealed that both types of cells express functional P2X7R. ATP and BzATP can promote proliferation, invasion, and metastasis after P2X7R activation; upregulate p-Akt, p-JNK, N-cadherin and vimentin; and downregulate E-cadherin compared with the control group, and the addition of the antagonist A438079 or oxATP or the knockdown of P2X7R could weaken these effects. The activation of P2X7R in breast cancer cells can promote their biological behaviors, indicating that P2X7R is a latent therapeutic target in breast cancer.

Epithelial-to-mesenchymal transition (EMT) is a biological process by which epithelial cells increase their motility and acquire invasive capacity. It represents a crucial driver of cancer metastasis and peritoneal dissemination. EMT plasticity, with cells exhibiting hybrid epithelial/mesenchymal states, and its reverse process, mesenchymal-to-epithelial transition (MET), allows them to adapt to different microenvironments and evade therapeutic intervention. Resistance to conventional treatments, including chemotherapy, is a major problem. Therapies targeting EMT may inhibit tumour cell migration and invasion, while affecting normal cells and repair mechanisms, resulting in potential side effects. This paper addresses the question of the impact of EMT status on cancers with potential spread to the peritoneum, which has remained unclear in literature. Relevant studies were selected from 2000 to 2024. Three macrosections were analysed: (i) pathological characteristics, (ii) surgical implications and (iii) oncological therapies. The focus was on survival and peritoneal recurrence time in patients who underwent surgical treatment.

Globally, prostate cancer is the second most common malignancy in males, with over 400 thousand men dying from the disease each year. A common treatment modality for localized prostate cancer is radiotherapy. However, up to half of high-risk patients can relapse with radiorecurrent prostate cancer, the aggressive clinical progression of which remains severely understudied. To address this, we have established an orthotopic mouse model for study that recapitulates the aggressive clinical progression of radiorecurrent prostate cancer. Radiorecurrent DU145 cells which survived conventional fraction (CF) irradiation were orthotopically injected into the prostates of athymic nude mice and monitored with bioluminescent imaging. CF tumours exhibited higher take rates and grew more rapidly than treatment-naïve parental tumours (PAR). Pathohistological analysis revealed extensive seminal vesicle invasion and necrosis in CF tumours, recapitulating the aggressive progression towards locally advanced disease exhibited by radiorecurrent tumours clinically. RNA sequencing of CF and PAR tumours identified ROBO1, CAV1, and CDH1 as candidate targets of radiorecurrent progression associated with biochemical relapse clinically. Together, this study presents a clinically relevant orthotopic model of radiorecurrent prostate cancer progression that will enable discovery of targets for therapeutic intervention to improve outcomes in prostate cancer patients.

Fibroblasts undergo metabolic reprogramming after contact with cancer cells in tumor microenvironment, producing lactate to provide a metabolic substrate for neighboring tumor cells. The exchange of lactate between cancer cells and fibroblasts via monocarboxylate transporters (MCTs) is known as the lactate shuttle. Colorectal cancer cells may establish a metabolic coupling akin to the lactate shuttle in collaboration with cancer-associated fibroblasts (CAFs) to augment their invasive and migratory capabilities. However, the specific phenomena and underlying mechanisms are not clear. In this study, we investigated the phenomena and explored the correlation and possible mechanism between CAFs and the invasion and migration of colorectal cancer cells by using two different co-culture models. The results showed that colorectal cancer cells established a lactate metabolic coupling with fibroblasts through the oxidative stress effect, triggering the metabolic reprogramming process of themselves and those of fibroblasts. In addition, lactate enhanced the invasion and migration of colorectal cancer by stabilizing the protein expression levels of nuclear factor kappa-B (NF-κB) and hypoxia-inducible factor-1α (HIF-1α). Blocking oxidative stress and lactate metabolic coupling with reactive oxygen species removers and MCT1-specific inhibitors, respectively, could effectively suppress metastasis in colorectal cancer. These findings suggest that targeting the lactate metabolic coupling between tumor cells and CAFs will offer a new strategy to combat colorectal cancer.

METTL3, an m6A methyltransferase, is integral to the regulation of messenger RNA (mRNA) biogenesis, degradation, and translation through the N6-methyladenosine (m6A) modification. Alterations in m6A homeostasis have been implicated in the development, progression, invasion, and metastasis of certain cancers. The present research aims to examine the consequences of METTL3 knockdown using short hairpin RNA (shRNA) on the proliferation and invasive capabilities of human colorectal and melanoma cancer cell lines. A specific shRNA against METTL3 mRNA was designed and inserted into an expression vector. Highly invasive colorectal cancer cell line SW480 and melanoma cell line A375 were cultured and transfected by METTL3-shRNA and scramble-control vectors and kept under culture condition for 2 weeks. The cells were harvested for analysis of gene expression by quantitative polymerase chain reaction (qPCR), invasion assay using three-dimensional (3D) spheroid assay and cell cycle and apoptosis analyses. In the METTL3-shRNA transfected cells, the expression of METTL3, VIM, SNAI1, SNAI2, ZEB1, CDH1, and TGFB1 genes were downregulated significantly compared with the scramble-control transfected cells. Expression of b-catenin, N-cadherin, vimentin, ZEB1, pro- and active MMP2, OCT4A, SOX2, and MYC proteins were also downregulated following METTL3 knockdown. Transfection by METTL3-shRNA reduced proliferation rate of the cells and increased the apoptotic rate significantly. Both migration and invasion rate of the cancer cells transfected with METTL3-shRNA were significantly decreased. These findings highlight the pro-oncogenic function of METTL3 in colorectal and melanoma cancer cells, indicating that inhibiting METTL3 could be a promising approach for tumor suppression across multiple cancer types; nonetheless, further investigation is essential to confirm these observations.

Adamantinomatous craniopharyngiomas (ACP) are rare epithelial tumors, which by the WHO are classified as non-malignant tumors. Despite radical tumor regression, almost 57% of patients develop a craniopharyngioma recurrence. The pathogenesis of epithelial cancers involves a process called epithelial-mesenchymal transition (EMT), which is involved in tumor progression and its invasion, and the loss of E-cadherin is crucial for this process. Undoubtedly, EMT also plays a role in the progression of ACP, but there are no studies that would examine its role in predicting postoperative tumor recurrence. Therefore, in our study, we aimed to compare the expression of EMT inducers and their markers, namely E-cadherin and vimentin, in material from two groups of pediatric patients, first with postoperative ACP relapse and second without relapse.

A total of 35 formalin-fixed, paraffin-embedded tissue blocks of pediatric patients (19 girls and 16 boys, from 2 to 17 years old) were included. The material was collected during craniopharyngioma resection in the years 2000-2019 and after then examined by the Department of Pathomorphology. Gene expression analysis was done using qRT-PCR.

In the studied group of 35 patients, high levels of E-cad and low levels of vimentin expression were found in patients who did not experience relapse (n = 25, p < 0.0001). The opposite was observed in patients who experienced a recurrence (n = 10, p < 0.0001). In contrast, analysis of the recurrent tissue itself showed low levels of vimentin and re-expression of E-cadherin (n = 10, p < 0.0001). Furthermore, our study shows that Snail is a key inducer of EMT in ACP.

We believe that the evaluation of the EMT profile in ACP could be a prognostic marker for predicting tumor recurrence in children, which would certainly contribute to a better prognosis for these patients.

Germ cell tumors (GCTs) constitute diverse neoplasms arising in the gonads or extragonadal locations. Testicular GCTs (TGCTs) are the predominant solid tumors in adolescents and young men. Despite cisplatin serving as the primary therapeutic intervention for TGCTs, 10‑20% of patients with advanced disease demonstrate resistance to cisplatin‑based chemotherapy, and epithelial‑mesenchymal transition (EMT) is a potential contributor to this resistance. EMT is regulated by various factors, including the snail family transcriptional repressor 2 (SLUG) transcriptional factor, and, to the best of our knowledge, remains unexplored within TGCTs. Therefore, the present study investigated the EMT transcription factor SLUG in TGCTs. In silico analyses were performed to investigate the expression of EMT markers in TGCTs. In addition, a cisplatin‑resistant model for TGCTs was developed using the NTERA‑2 cell line, and a mouse model was also established. Subsequently, EMT was assessed both in vitro and in vivo within the cisplatin‑resistant models using quantitative PCR and western blot analyses. The results of the in silico analysis showed that the different histologies exhibited distinct expression profiles for EMT markers. Seminomas exhibited a lower expression of EMT markers, whereas embryonal carcinomas and mixed GCT demonstrated high expression. Notably, patients with lower SLUG expression had longer median progression‑free survival (46.4 months vs. 28.0 months, P=0.022). In the in vitro analysis, EMT‑associated genes [fibronectin; vimentin (VIM); actin, α2, smooth muscle; collagen type I α1; transforming growth factor‑β1; and SLUG] were upregulated in the cisplatin‑resistant NTERA‑2 (NTERA‑2R) cell line after 72 h of cisplatin treatment. Consistent with this finding, the NTERA‑2R mouse model demonstrated a significant upregulation in the expression levels of VIM and SLUG. In conclusion, the present findings suggested that SLUG may serve a crucial role in connecting EMT with the development of cisplatin resistance, and targeting SLUG may be a putative therapeutic strategy to mitigate cisplatin resistance.

Testicular germ cell tumor (TGCT) is a common malignant tumor in adolescents. Now, many long non-coding RNAs (LncRNAs) have been found to have an important function in TGCT. LINC00470 is specifically and highly expressed in TGCT, however, there is still no definite information concerning its role and underlying mechanism in TGCT. The purpose of this research was to look into the involvement of LINC00470 in TGCT and its intrinsic mechanism.

UCSC and GEPIA2 databases were used to analyze the expression of LINC00470, and the BEST website was used to perform GSEA enrichment analysis, immune infiltration analysis, and drug susceptibility analysis. SiRNA transfection was used to silence LINC00470 in TCAM-2 and NCCIT cells. Clone formation and Transwell assays were performed in TGCT cells to confirm the effects of LINC00470 on clone formation, migration, and invasion. Western Blot was performed to determine the expression of proteins related to the EMT and AKT signaling pathways. LINC00470 was specifically highly expressed in TGCT, and played a role in promoting tumor cell clone formation and cell metastasis by affecting the TGF-β and PI3K-AKT-mTOR signaling pathways to regulate the epithelial-mesenchymal transition (EMT) process; LINC00470 may also play a pro-tumor role by negatively regulating immune infiltration; in addition, the expression of LINC00470 was negatively correlated with the chemosensitivity of cisplatin in TGCT patients.

LINC00470 may play a significant role in the etiology and metastasis of TGCT through EMT and AKT-mediated signaling pathways.

Background/Objectives: Biliary tract cancer (BTC) is a rare but aggressive malignancy that requires surgical treatment. However, postoperative recurrence rates are high, and reliable predictors of recurrence are limited. This study aimed to investigate the effectiveness of cell-free DNA (cfDNA) and circulating tumor cells (CTCs) in predicting early recurrence after curative surgery and complete adjuvant therapy in patients with BTC. Methods: Twenty-four patients who underwent R0 and R1 resections and completed adjuvant therapy for BTC between September 2019 and March 2022 were followed up until March 2024. Patients were categorized into early recurrence (ER) and non-ER groups, using one year as the cutoff for recurrence. Results: The combination score derived from ultrashort fragments of cfDNA, vimentin-positive CTCs, and carbohydrate antigen (CA) 19-9 levels showed a statistically significant difference between the ER and non-ER groups (p-value < 0.001). The receiver operating characteristic curve from the combination score and CA 19-9 levels yielded areas under the curve of 0.891 and 0.750, respectively. Conclusions: Although further research is required, these findings suggest that cfDNA and CTCs may increase the accuracy of predicting postoperative recurrence in patients with BTC.

The MET receptor, commonly known as HGF (hepatocyte growth factor) receptor, is a focus of extensive scientific research. MET has been linked to embryonic development, tissue regeneration following injury, tumorigenesis, and cancer metastasis. These functions underscore its involvement in numerous cellular processes, including stemness, proliferation, motility, cell dissociation, and survival. However, the enigmatic nature of MET becomes apparent in the context of cancer. When MET remains persistently activated, since its gene undergoes genetic alterations, it initiates a complex signaling cascade setting in motion an aggressive and metastatic program that is characteristic of malignant cells and is known as "invasive growth". The expanding knowledge of MET signaling has opened up numerous opportunities for therapeutic interventions, particularly in the realm of oncology. Targeting MET presents a promising strategy for developing novel anti-cancer treatments. In this review, we provide an updated overview of drugs designed to modulate MET signaling, highlighting MET kinase inhibitors, degraders, anti-MET/HGF monoclonal antibodies, and MET-targeted antibody-drug conjugates. Through this review, we aim to contribute to the ongoing advancement of therapeutic strategies targeting MET signaling.

Tumor cell invasion is considered as one of the main therapeutic challenges in cancer patients, which leads to distant metastasis and reduced prognosis. Therefore, investigation of the factors involved in tumor cell invasion improves the therapeutic methods to reduce tumor metastasis. Epithelial-mesenchymal transition (EMT) process has a pivotal role in tumor cell invasion and metastasis, during which tumor cells gain the invasive ability by losing epithelial characteristics and acquiring mesenchymal characteristics. WNT/β-catenin signaling pathway has a key role in tumor cell invasion by regulation of EMT process. Long non-coding RNAs (lncRNAs) have also an important role in EMT process through the regulation of WNT/β-catenin pathway. Deregulation of lncRNAs is associated with tumor metastasis in different tumor types. Therefore, in the present review, we investigated the role of lncRNAs in EMT process and tumor cell invasion through the regulation of WNT/β-catenin pathway. It has been reported that lncRNAs mainly induced the EMT process and tumor cell invasion through the activation of WNT/β-catenin pathway. LncRNAs that regulate the WNT/β-catenin mediated EMT process can be introduced as the prognostic markers as well as suitable therapeutic targets to reduce the tumor metastasis in cancer patients.

Significance: Reduction-oxidation (redox) regulation is an important biological phenomenon that provides a balance between antioxidants and the generation of reactive oxygen species and reactive nitrogen species under pathophysiological conditions. Structural and functional changes in glycans are also important as post-translational modifications of proteins. The integration of glycobiology and redox biology, called glyco-redox has provided new insights into the mechanisms of epithelial-mesenchymal transition (EMT)/mesenchymal-epithelial transition (MET), cancer, and various diseases including Alzheimer's disease, chronic obstructive lung disease, type 2 diabetes, interstitial pneumonitis, and ulcerative colitis. Recent Advances: Glycans are biosynthesized by specific glycosyltransferases and each glycosyltransferase is either directly or indirectly regulated by oxidative stress and redox regulation. A typical example of glyco-redox is the role of N-glycan referred to as core fucose in superoxide dismutase 3. This glycan was found to be involved in the growth inhibition of cancer cell lines. Critical Issues: The significance of glyco-redox in EMT/MET, cancer, and various diseases was found in major N-glycan branching glycosyltransferases β1,4N-acetylglucosaminyltransferase III, β1,4N-acetylglucosaminyltransferase IV, β1,6N-acetylglucosaminyltransferase V, β1,4-acetylglucosaminyltransfearfse VI, β1,6-acetylglucosaminyltransferase IX, α-1,6 fucosyltransferase, and β-galactoside α-2,6-sialyltransferase 1. Herein, we summarize previous reports on target proteins and how this relates to oxidative stress. We also discuss the products of these processes and their significance to cancer and various diseases. Future Direction: A clear-cut understanding of the significance of glyco-redox in relation to prevention, diagnosis, and therapeutics is required. These studies will open a new road toward glycobiology and redox biology. Antioxid. Redox Signal. 41, 910-926.

The nucleus is the organelle of the cell responsible for controlling protein expression, which has a direct effect on cellular biological functions. Here we show that the cytoskeletal protein vimentin plays an important role in increasing cell-generated forces transmitted to the cell nucleus, resulting in increased nuclear deformations in strongly polarized cells. Using micropatterned substrates to geometrically control cell shape in wild-type and vimentin-null cells, we show vimentin increases polarization and deformation of the cell nucleus. Loss of nesprin-3, which physically couples vimentin to the nuclear envelope, phenotypically copies the loss of vimentin, suggesting vimentin transmits forces to the cell nucleus through direct molecular linkages. Use of a fluorescence resonance energy transfer (FRET) sensor that binds to the nuclear envelope through lamin-A/C suggests vimentin increases the tension on the nuclear envelope. Our results indicate that nuclear shape and deformation can be modified by the vimentin cytoskeleton and its specific crosslinks to the cell nucleus.

As a structural protein, keratin is mainly expressed in epithelial cells and skin appendages to provide mechanical support and external resistance. The keratin family has a total of 54 members, which are divided into type I and type II. Two types of keratins connect to each other to form keratin intermediate filaments and participate in the construction of the cytoskeleton. K18 is a non-hair keratin, which is widely expressed in simple epithelial tissues with its partner, K8. Compared with mechanical support, K8/K18 pairs play more important roles in biological regulation, such as mediating anti-apoptosis, regulating cell cycle progression, and transmitting signals. Mutations in K18 can cause a variety of non-neoplastic diseases of the visceral epithelium. In addition, the expression levels of K18 are frequently altered in various epithelial-derived tumors, especially adenocarcinomas, which suggests that K18 may be involved in tumorigenesis. Due to the specific expression pattern of K18 in tumor tissues and its serum level reflecting tumor cell death, apply K18 to diagnose tumors and predict its prognosis have the potential to be simple and effective alternative methods. However, these potential roles of K18 in tumors have not been fully summarized. In this review, we focus on the relationship between K18 and epithelial-derived tumors, discuss the value of K18 as a diagnostic and prognostic marker, and summarize the interactions of K18 with various related proteins in tumorigenesis, with examples of simple epithelial tumors such as lung, breast, liver, and gastrointestinal cancers.

Cancer stem cells (CSCs) are widely acknowledged as the drivers of tumor initiation, epithelial-mesenchymal transition (EMT) progression, and metastasis. Originating from both hematologic and solid malignancies, CSCs exhibit quiescence, pluripotency, and self-renewal akin to normal stem cells, thus orchestrating tumor heterogeneity and growth. Through a dynamic interplay with the tumor microenvironment (TME) and intricate signaling cascades, CSCs undergo transitions from differentiated cancer cells, culminating in therapy resistance and disease recurrence. This review undertakes an in-depth analysis of the multifaceted mechanisms underlying cancer stemness and CSC-mediated resistance to therapy. Intrinsic factors encompassing the TME, hypoxic conditions, and oxidative stress, alongside extrinsic processes such as drug efflux mechanisms, collectively contribute to therapeutic resistance. An exploration into key signaling pathways, including JAK/STAT, WNT, NOTCH, and HEDGEHOG, sheds light on their pivotal roles in sustaining CSCs phenotypes. Insights gleaned from preclinical and clinical studies hold promise in refining drug discovery efforts and optimizing therapeutic interventions, especially chimeric antigen receptor (CAR)-T cell therapy, cytokine-induced killer (CIK) cell therapy, natural killer (NK) cell-mediated CSC-targeting and others. Ultimately use of cell sorting and single cell sequencing approaches for elucidating the fundamental characteristics and resistance mechanisms inherent in CSCs will enhance our comprehension of CSC and intratumor heterogeneity, which ultimately would inform about tailored and personalized interventions.

To evaluate the suitability of the MIA PaCa-2 cell line for studying pancreatic cancer intratumor heterogeneity, we aim to further characterize the nature of MIA PaCa-2 cells' phenotypic, genomic, and transcriptomic heterogeneity.

MIA PaCa-2 single-cell clones were established through flow cytometry. For the phenotypic study, we quantified the cellular morphology, proliferation rate, migration potential, and drug sensitivity of the clones. The chromosome copy number and transcriptomic profiles were quantified using SNPa and RNA-seq, respectively.

Four MIA PaCa-2 clones showed distinctive phenotypes, with differences in cellular morphology, proliferation rate, migration potential, and drug sensitivity. We also observed a degree of genomic variations between these clones in form of chromosome copy number alterations and single nucleotide variations, suggesting the genomic heterogeneity of the population, and the intrinsic genomic instability of MIA PaCa-2 cells. Lastly, transcriptomic analysis of the clones also revealed gene expression profile differences between the clones, including the uniquely regulated ITGAV , which dictates the morphology of MIA PaCa-2 clones.

MIA PaCa-2 is comprised of cells with distinctive phenotypes, heterogeneous genomes, and differential transcriptomic profiles, suggesting its suitability as a model to study the underlying mechanisms behind pancreatic cancer heterogeneity.

The switch/sucrose non-fermentable (SWI/SNF) subfamily are evolutionarily conserved, ATP-dependent chromatin-remodelling complexes that alter nucleosome position and regulate a spectrum of nuclear processes, including gene expression, DNA replication, DNA damage repair, genome stability and tumour suppression. These complexes, through their ATP-dependent chromatin remodelling, contribute to the dynamic regulation of genetic information and the maintenance of cellular processes essential for normal cellular function and overall genomic integrity. Mutations in SWI/SNF subunits are detected in 25% of human malignancies, indicating that efficient functioning of this complex is required to prevent tumourigenesis in diverse tissues. During development, SWI/SNF subunits help establish and maintain gene expression patterns essential for proper cellular identity and function, including maintenance of lineage-specific enhancers. Moreover, specific molecular signatures associated with SWI/SNF mutations, including disruption of SWI/SNF activity at enhancers, evasion of G0 cell cycle arrest, induction of cellular plasticity through pro-oncogene activation and Polycomb group (PcG) complex antagonism, are linked to the initiation and progression of carcinogenesis. Here, we review the molecular insights into the aetiology of human malignancies driven by disruption of the SWI/SNF complex and correlate these mechanisms to their developmental functions. Finally, we discuss the therapeutic potential of targeting SWI/SNF subunits in cancer.

The expression of markers associated with epithelial-mesenchymal transition (EMT) and extracellular matrix degradation in human uveal melanoma tissue samples and postequatorial zone of the choroid was assessed by immunohistochemical staining. Increased expression of EMT markers E-cadherin and vimentin was observed in the tumor. The ratio of MMP-9 to TIMP-1 proteins related to the extracellular matrix degradation was higher in the tumor. These results may indicate activation of EMT-like process in the uveal melanoma cells and degradation of the extracellular matrix, which can contribute to the development of collective invasion in uveal melanoma.

Metastasis frequently targets bones, where cancer cells from the primary tumour migrate to the bone marrow, initiating new tumour growth. Not only is bone the most common site for metastasis, but it also often marks the first site of metastatic recurrence. Despite causing over 90% of cancer-related deaths, effective treatments for bone metastasis are lacking, with current approaches mainly focusing on palliative care. Circulating tumour cells (CTCs) are pivotal in metastasis, originating from primary tumours and circulating in the bloodstream. They facilitate metastasis through molecular interactions with the bone marrow environment, involving direct cell-to-cell contacts and signalling molecules. CTCs infiltrate the bone marrow, transforming into disseminated tumour cells (DTCs). While some DTCs remain dormant, others become activated, leading to metastatic growth. The presence of DTCs in the bone marrow strongly correlates with future bone and visceral metastases. Research on CTCs in peripheral blood has shed light on their release mechanisms, yet investigations into bone marrow DTCs have been limited. Challenges include the invasiveness of bone marrow aspiration and the rarity of DTCs, complicating their isolation. However, advancements in single-cell analysis have facilitated insights into these elusive cells. This review will summarize recent advancements in understanding bone marrow DTCs using single-cell analysis techniques.

Gastric cancer (GC) ranks as the fifth most prevalent cancer globally, and its pronounced invasiveness and propensity to spread provide significant challenges for therapy. At present, there are no efficacious medications available for the treatment of patients with GC. Isoliensinine (ISO), a bisbenzylisoquinoline alkaloid, was isolated from Nelumbo nucifera Gaertn. It possesses anti-tumor, antioxidant, and other physiological effects. Nevertheless, there is currently no available study on the impact of ISO on GC, and further investigation is needed to understand its molecular mechanism.

ISO target points and GC-related genes were identified, and the cross-target points of ISO and GC were obtained. We then examined cross-targeting and found genes that were differentially expressed in GCs. Kaplan-Meier survival curves were used to screen target genes, and the STRING database and Cytoscape 3.9.1 were used to construct protein-protein interactions and drug-target networks. In addition, molecular docking studies confirmed the interactions between ISO screen targets. Finally, in vitro tests were used to establish the impact of ISO on GC cells.

Through bioinformatics research, we have identified TGFBR1 as the target of ISO in GC. In addition, we noticed a substantial inhibition in GC cell proliferation, migration, and invasion activities following ISO treatment. Moreover, we noticed that ISO treatment effectively suppressed TGF-β-induced epithelial-mesenchymal transition (EMT) and activation of the TGF-β-Smad pathway. Furthermore, we discovered that siTGFBR1 nullified the impact of ISO on TGF-β-triggered migration, invasion, and activation of the TGF-β-Smad pathway.

Our research suggests that ISO specifically targets TGFBR1 and regulates the TGF-β-Smad signaling pathway to suppress the proliferation and migration of GC cells.

Untreated primary carcinomas often lead to progression, invasion and metastasis, a process that involves the epithelial-to-mesenchymal transition (EMT). Several transcription factors (TFs) mediate the development of EMT, including SNAIL1/SNAIL2, TWIST1/TWIST2 and ZEB1/ZEB2, which are overexpressed in various carcinomas along with the under expression of the metastasis suppressor Raf Kinase Inhibitor Protein (RKIP). Overexpression of RKIP inhibits EMT and the above associated TFs. We, therefore, hypothesized that there are inhibitory cross-talk signaling pathways between RKIP and these TFs. Accordingly, we analyzed the various properties and biomarkers associated with the epithelial and mesenchymal tissues and the various molecular signaling pathways that trigger the EMT phenotype such as the TGF-β, the RTK and the Wnt pathways. We also presented the various functions and the transcriptional, post-transcriptional and epigenetic regulations for the expression of each of the EMT TFs. Likewise, we describe the transcriptional, post-transcriptional and epigenetic regulations of RKIP expression. Various signaling pathways mediated by RKIP, including the Raf/MEK/ERK pathway, inhibit the TFs associated with EMT and the stabilization of epithelial E-Cadherin expression. The inverse relationship between RKIP and the TF expressions and the cross-talks were further analyzed by bioinformatic analysis. High mRNA levels of RKIP correlated negatively with those of SNAIL1, SNAIL2, TWIST1, TWIST2, ZEB1, and ZEB2 in several but not all carcinomas. However, in these carcinomas, high levels of RKIP were associated with good prognosis, whereas high levels of the above transcription factors were associated with poor prognosis. Based on the inverse relationship between RKIP and EMT TFs, it is postulated that the expression level of RKIP in various carcinomas is clinically relevant as both a prognostic and diagnostic biomarker. In addition, targeting RKIP induction by agonists, gene therapy and immunotherapy will result not only in the inhibition of EMT and metastases in carcinomas, but also in the inhibition of tumor growth and reversal of resistance to various therapeutic strategies. However, such targeting strategies must be better investigated as a result of tumor heterogeneities and inherent resistance and should be better adapted as personalized medicine.

Cancer stem cells (CSCs) represent a subpopulation of cancer cells that are believed to initiate and drive cancer progression. In animal models, xenotransplanted CSCs have demonstrated the ability to produce tumors. Since their initial isolation in blood cancers, CSCs have been identified in various solid human cancers, including oral squamous cell carcinoma (OSCC). In addition to their tumorigenic properties, dysregulated stem-cell-related signaling pathways-Wnt family member (Wnt), neurogenic locus notch homolog protein (Notch), and hedgehog-have been shown to endow CSCs with characteristics like self-renewal, phenotypic plasticity, and chemoresistance, contributing to recurrence and treatment failure. Consequently, CSCs have become targets for new therapeutic agents, with some currently in different phases of clinical trials. Notably, small molecule inhibitors of the hedgehog signaling pathway, such as vismodegib and glasdegib, have been approved for the treatment of basal cell carcinoma and acute myeloid leukemia, respectively. Other strategies for eradicating CSCs include natural compounds, nano-drug delivery systems, targeting mitochondria and the CSC microenvironment, autophagy, hyperthermia, and immunotherapy. Despite the extensive documentation of CSCs in OSCC since its first demonstration in head and neck (HN) SCC in 2007, none of these novel pharmacological approaches have yet entered clinical trials for OSCC patients. This narrative review summarizes the in vivo and in vitro evidence of CSCs and CSC-related signaling pathways in OSCC, highlighting their role in promoting chemoresistance and immunotherapy resistance. Additionally, it addresses methodological challenges and discusses future research directions to improve experimental systems and advance CSC studies.