The FAT atypical cadherin 1 (FAT1) gene is the ortholog of the Drosophila fat gene and encodes the protocadherin FAT1. FAT1 belongs to the cadherin superfamily, a group of full-length membrane proteins that contain cadherin-like repeats. In various types of human cancer, FAT1 is one of the most commonly mutated genes, and is considered to be an emerging cancer biomarker and a potential target for novel therapies. However, the biological functions of FAT1 and the precise downstream signaling pathways that it mediates have remained to be fully elucidated. The present review discussed the current literature on FAT1, focusing on FAT1 mutations and expression levels, and their impact on signaling pathways and mechanisms in various types of cancer, including both solid tumors and hematological malignancies, such as esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, hepatocellular carcinoma, glioma, breast cancer, acute lymphoblastic leukemia, acute myeloid leukemia, lymphoma and myeloma. The present review aimed to provide further insights and research directions for future studies on FAT1 as an oncogenic factor or tumor suppressor.

Histone acetylation modifications can regulate gene transcription and play crucial roles in multiple tumorigeneses processes. YEATS domain proteins are one important type of acetylation readers. We have found significant mutations and copy number amplifications of YEATS domain containing 2 (YEATS2) gene in esophageal squamous cell carcinoma (ESCC) through whole genome sequencing (WGS). However, the function and molecular mechanism of YEATS2 in ESCC remain elusive.

Chi-squared test and Kaplan-Meier methods were used to analyze the clinical significance of YEATS2. MTT, Colony Formation Assay, Transwell, Scratch Wound Healing, subcutaneous tumorigenesis model and lung metastatic tumor model were performed to detect YEATS2 effect on the proliferation and migration ability of ESCC cells in vivo and in vitro Co-IP-based mass spectrum (MS) assays and Chromatin immunoprecipitation (ChIP) were performed to explore the molecular mechanism of YEATS2 function in ESCC.

ESCC patients with copy number amplification of YEATS2 had shorter postoperative survival. Furthermore, YEATS2 expression was positively correlated with copy number amplification. We have also found that YEATS2 expression was significantly upregulated in ESCC tissues and was correlated closely with the differentiation degree of ESCC cells. The results of in vivo and in vitro experiments revealed that YEATS2 enhanced the abilities of ESCC cells to proliferate and migrate. Mechanistically, YEATS2 activated NF-κB signaling to promote ESCC progression. YEATS2 and H3K27 acetylation (H3K27ac) were both enriched in the promoter region of IL6ST, which is involved in the regulation of YEATS2 on NF-κB signaling. Additionally, YEATS2 could recruit TAF15 and KAT5 to enhance H3K27ac enrichment in the promoter region of IL6ST to regulate its expression.

In conclusion, YEATS2 might function as a potential driver gene and a potential therapeutic target in ESCC.

The objective was to determine whether USP13 stabilizes WISP1 protein and contributes to tumorigenicity and metastasis in ESCC through the Wnt/CTNNB1 signaling pathway. ESCC cell lines (KYSE150 and TE10) were treated with the proteasome inhibitor MG-132, followed by siRNA screening of deubiquitinases (DUBs) to identify regulators of WISP1. Mass spectrometry, immunoprecipitation, and in vitro functional assays were conducted to explore the interaction between USP13 and WISP1 and to assess the effects of USP13 downregulation on cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and apoptosis. Additionally, in vivo experiments using mouse models were performed to evaluate the impact of USP13 knockdown on tumor growth and metastasis. USP13 was identified as a key regulator of WISP1, stabilizing its protein levels through deubiquitination. Downregulation of USP13 resulted in reduced WISP1 protein stability, decreased cell proliferation, migration, and EMT, and increased apoptosis in vitro. In vivo, USP13 knockdown significantly inhibited tumor growth and lung metastasis. WISP1 overexpression in USP13-knockdown cells partially rescued these phenotypes, confirming the functional role of the USP13/WISP1 axis. Furthermore, knockdown of USP13 or WISP1 impaired the activation of the Wnt/CTNNB1 signaling pathway and reduced immune checkpoint marker expression, indicating a mechanism by which USP13 promotes immune evasion in ESCC. USP13 stabilizes WISP1 through deubiquitination, enhancing ESCC progression by activating the Wnt/CTNNB1 pathway and promoting immune evasion, making USP13 a potential therapeutic target in ESCC.

Drug export through ABC proteins hinders cancer response to chemotherapy. Here, we have evaluated the relevance of MRP3 (ABCC3) in cholangiocarcinoma (CCA) as a potential target to overcome drug resistance.

Gene expression was analyzed in silico using the TCGA-CHOL database and experimentally (mRNA and protein) in resected CCA tumors. The effect of manipulating MRP3 function/expression was evaluated in vitro and in vivo.

High MRP3 expression at the plasma membrane of human CCA cells was found. MRP3 overexpression in HEK293T cells selectively impaired the cytotoxic effect of etoposide, cisplatin, SN-38, and mitoxantrone. Reduced MRP3 activity with shRNAs or pan-MRP blockers enhanced the sensitivity to these drugs. MRP3 interaction with natural and semisynthetic compounds (≈40,000) was evaluated by virtual drug screening and molecular docking. Two identified potential MRP3 inhibitors (EM-114, EM-188), and sorafenib impaired MRP3 transport activity and enhanced sensitivity of CCA cells to etoposide and cisplatin. The antitumor effect of cisplatin in the mouse xenograft model was enhanced by co-treatment with sorafenib, which was accompanied by a higher intratumor accumulation of cisplatin.

Genetic and pharmacological MRP3 inhibition enhances the anti-CCA effect of several drugs, which constitutes a promising strategy to improve the response to chemotherapy in CCA patients.

Breakthrough symptoms are thought to occur in roughly half of all gastroesophageal reflux disease (GERD) patients despite maximal acid suppression (proton pump inhibitor, PPI) therapy. Topical alginates have recently been shown to enhance mucosal defense against acid-pepsin insult during GERD. We aimed to examine potential alginate protection of transcriptomic changes in a cell culture model of PPI-recalcitrant GERD. Immortalized normal-derived human esophageal epithelial cells underwent pretreatment with commercial alginate-based anti-reflux medications (Gaviscon Advance or Gaviscon Double Action), a matched-viscosity placebo control, or pH 7.4 buffer (sham) alone for 1 min, followed by exposure to pH 6.0 + pepsin or buffer alone for 3 min. RNA sequencing was conducted, and Ingenuity Pathway Analysis was performed with a false discovery rate of ≤0.01 and absolute fold-change of ≥1.3. Pepsin-acid exposure disrupted gene expressions associated with epithelial barrier function, chromatin structure, carcinogenesis, and inflammation. Alginate formulations demonstrated protection by mitigating these changes and promoting extracellular matrix repair, downregulating proto-oncogenes, and enhancing tumor suppressor expression. These data suggest molecular mechanisms by which alginates provide topical protection against injury during weakly acidic reflux and support a potential role for alginates in the prevention of GERD-related carcinogenesis.

Esophageal Cancer (EC) ranks among the most common malignancies worldwide. Most EC patients acquire drug resistance to chemotherapy either intrinsically or acquired after T-DM1 treatment, which shows that increasing or decreasing the expression of particular genes might influence chemotherapeutic sensitivity or resistance. Therefore, gaining a deeper understanding of the altered expression of genes involved in EC drug resistance and developing new therapeutic methods are essential targets for continued advancement in EC therapy.

The present study aimed to find critical regulatory genes/pathways in the progression of T-DM1 resistance in OE-19 EC cells. Expression datasets were extracted from GEO omnibus. Gene interactions were analyzed, and the protein-protein interaction network was drawn. Then, enrichment analysis of the hub genes and network cluster analysis of the hub genes was performed. Finally, the genes were screened in the DrugBank database as therapeutic targets and molecular docking analysis was done on the selected targets.

In the current study, nine hub genes were identified in TDM-1-resistant EC cells (CTGF, CDH17, THBS1, CXCL8, NRP1, ITGB5, EDN1, FAT1, and PTGS2). The KEGG analysis highlighted the IL-17 signaling pathway and ECM-receptor interaction pathway as the most critical pathways; cluster analysis also showed the significance of these pathways. Therefore, the genes involved in these two pathways, including CXCL8, FSCN1, PTGS2, SERPINE2, LEF1, THBS1, CCN2, TAGLN, CDH11, and ITGA6, were searched in DrugBank as therapeutic targets. The DrugBank analysis suggests a potential role for Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) in reducing T-DM1 drug resistance in EC. The docking results revealed that NSAIDs, including Diclofenac, Mefenamic acid, Celecoxib, Naproxen, and Etoricoxib, significantly suppress resistant cancer cells.

This comprehensive bioinformatics analysis deeply explains the molecular mechanisms governing TDM-1 resistance in EC. The identified hub genes and their associated pathways offer potential targets for therapeutic interventions. Moreover, the possible role of NSAIDs in mitigating T-DM1 resistance presents an intriguing avenue for further investigation. This research contributes significantly to the field and establishes a basis for further research to enhance treatment efficacy for EC patients.

Despite the challenges posed by drug resistance and side effects, chemotherapy remains a pivotal strategy in cancer treatment. A key issue in this context is macroautophagy (commonly known as autophagy), a dysregulated cell death mechanism often observed during chemotherapy. Autophagy plays a cytoprotective role by maintaining cellular homeostasis and recycling organelles, and emerging evidence points to its significant role in promoting cancer progression. Cisplatin, a DNA-intercalating agent known for inducing cell death and cell cycle arrest, often encounters resistance in chemotherapy treatments. Recent studies have shown that autophagy can contribute to cisplatin resistance or insensitivity in tumor cells through various mechanisms. This resistance can be mediated by protective autophagy, which suppresses apoptosis. Additionally, autophagy-related changes in tumor cell metastasis, particularly the induction of Epithelial-Mesenchymal Transition (EMT), can also lead to cisplatin resistance. Nevertheless, pharmacological strategies targeting the regulation of autophagy and apoptosis offer promising avenues to enhance cisplatin sensitivity in cancer therapy. Notably, numerous non-coding RNAs have been identified as regulators of autophagy in the context of cisplatin chemotherapy. Thus, therapeutic targeting of autophagy or its associated pathways holds potential for restoring cisplatin sensitivity, highlighting an important direction for future clinical research.

Emerging studies have shown that FAT atypical cadherin 1 (FAT1) and autophagy separately inhibits and promotes acute myeloid leukemia (AML) proliferation. However, it is unknown whether FAT1 were associated with autophagy in regulating AML proliferation.

AML cell lines, 6-week-old male nude mice and AML patient samples were used in this study. qPCR/Western blot and cell viability/3H-TdR incorporation assays were separately used to detect mRNA/protein levels and cell activity/proliferation. Luciferase reporter assay was used to examine gene promoter activity. Co-IP analysis was used to detect the binding of proteins.

In this study, we for the first time demonstrated that FAT1 inhibited AML proliferation by decreasing AML autophagy level. Moreover, FAT1 weakened AML autophagy level via decreasing autophagy related 4B (ATG4B) expression. Mechanistically, we found that FAT1 reduced the phosphorylated and intranuclear SMAD family member 2/3 (smad2/3) protein levels, thus decreasing the activity of ATG4B gene promoter. Furthermore, we found that FAT1 competitively bound to TGF-βR II which decreased the binding of TGF-βR II to TGF-βR I and the subsequent phosphorylation of TGF-βR I, thus reducing the phosphorylation and intranuclear smad2/3. The experiments in nude mice showed that knockdown of FAT1 promoted AML autophagy and proliferation in vivo.

Collectively, these results revealed that FAT1 downregulates ATG4B expression via inhibiting TGFβ-smad2/3 signaling activity, thus decreasing the autophagy level and proliferation activity of AML cells.

Our study suggested that the "FAT1-TGFβ-smad2/3-ATG4B-autophagy" pathway may be a novel target for developing new targeted drugs to AML treatment.

Although there has been some progress in the efficacy of anti-cancer drugs, drug resistance remains challenging. Cancer stem cells (CSCs) are self-renewing and differentiate into cancer tissues with tumor heterogeneity. CSCs are associated with the progression of breast, colon, and lung cancers. Hence, recent studies have focused on the role of CSCs in resistance to anti-cancer drugs. Increasing evidence suggests that CSCs interact with components of the tumor microenvironment (TME), such as vascular and immune cells, as well as various cytokines, and are regulated by multiple signaling pathways, thereby promoting drug resistance in various cancers. Therefore, it is important to clarify the mechanisms underlying the crosstalk between CSCs and the TME for the development of targeted anti-cancer therapies.

The fourth common reason of death among patients is gastric cancer (GC) and it is a dominant tumor type in Ease Asia. One of the problems in GC therapy is chemoresistance. Cisplatin (CP) is a platinum compound that causes DNA damage in reducing tumor progression and viability of cancer cells. However, due to hyperactivation of drug efflux pumps, dysregulation of genes and interactions in tumor microenvironment, tumor cells can develop resistance to CP chemotherapy. The current review focuses on the CP resistance emergence in GC cells with emphasizing on molecular pathways, pharmacological compounds for reversing chemoresistance and the role of nanostructures. Changes in cell death mechanisms such as upregulation of pro-survival autophagy can prevent CP-mediated apoptosis that results in drug resistance. Moreover, increase in metastasis via EMT induction induces CP resistance. Dysregulation of molecular pathways such as PTEN, PI3K/Akt, Nrf2 and others result in changes in CP response of GC cells. Non-coding RNAs determine CP response of GC cells and application of pharmacological compounds with activity distinct of CP can result in sensitivity in tumor cells. Due to efficacy of exosomes in transferring bioactive molecules such as RNA and DNA molecules among GC cells, exosomes can also result in CP resistance. One of the newest progresses in overcoming CP resistance in GC is application of nanoplatforms for delivery of CP in GC therapy that they can increase accumulation of CP at tumor site and by suppressing carcinogenic factors and overcoming biological barriers, they increase CP toxicity on cancer cells.

Esophageal squamous cell carcinoma (ESCC) has a poor prognosis and is one of the deadliest gastrointestinal malignancies. Despite numerous transcriptomics studies to understand its molecular basis, the impact of population-specific differences on this disease remains unexplored.

This study aimed to investigate the population-specific differences in gene expression patterns among ESCC samples obtained from six distinct global populations, identify differentially expressed genes (DEGs) and their associated pathways, and identify potential biomarkers for ESCC diagnosis and prognosis. In addition, this study deciphers population specific microbial and chemical risk factors in ESCC.

We compared the gene expression patterns of ESCC samples from six different global populations by analyzing microarray datasets. To identify DEGs, we conducted stringent quality control and employed linear modeling. We cross-compared the resulting DEG lists of each populations along with ESCC ATLAS to identify known and novel DEGs. We performed a survival analysis using The Cancer Genome Atlas Program (TCGA) data to identify potential biomarkers for ESCC diagnosis and prognosis among the novel DEGs. Finally, we performed comparative functional enrichment and toxicogenomic analysis.

Here we report 19 genes with distinct expression patterns among populations, indicating population-specific variations in ESCC. Additionally, we discovered 166 novel DEGs, such as ENDOU, SLCO1B3, KCNS3, IFI35, among others. The survival analysis identified three novel genes (CHRM3, CREG2, H2AC6) critical for ESCC survival. Notably, our findings showed that ECM-related gene ontology terms and pathways were significantly enriched among the DEGs in ESCC. We also found population-specific variations in immune response and microbial infection-related pathways which included genes enriched for HPV, Ameobiosis, Leishmaniosis, and Human Cytomegaloviruses. Our toxicogenomic analysis identified tobacco smoking as the primary risk factor and cisplatin as the main drug chemical interacting with the maximum number of DEGs across populations.

This study provides new insights into population-specific differences in gene expression patterns and their associated pathways in ESCC. Our findings suggest that changes in extracellular matrix (ECM) organization may be crucial to the development and progression of this cancer, and that environmental and genetic factors play important roles in the disease. The novel DEGs identified may serve as potential biomarkers for diagnosis, prognosis and treatment.

Failure to achieve complete elimination of triple negative breast cancer (TNBC) stem cells after adjuvant therapy is associated with poor outcomes. Aldehyde dehydrogenase 1 (ALDH1) is a marker of breast cancer stem cells (BCSCs), and its enzymatic activity regulates tumor stemness. Identifying upstream targets to control ALDH+ cells may facilitate TNBC tumor suppression. Here, we show that KK-LC-1 determines the stemness of TNBC ALDH+ cells via binding with FAT1 and subsequently promoting its ubiquitination and degradation. This compromises the Hippo pathway and leads to nuclear translocation of YAP1 and ALDH1A1 transcription. These findings identify the KK-LC-1-FAT1-Hippo-ALDH1A1 pathway in TNBC ALDH+ cells as a therapeutic target. To reverse the malignancy due to KK-LC-1 expression, we employ a computational approach and discover Z839878730 (Z8) as an small-molecule inhibitor which may disrupt KK-LC-1 and FAT1 binding. We demonstrate that Z8 suppresses TNBC tumor growth via a mechanism that reactivates the Hippo pathway and decreases TNBC ALDH+ cell stemness and viability.

The FAT cadherin family members (FAT1, FAT2, FAT3 and FAT4) are conserved tumor suppressors that are recurrently mutated in several types of human cancers, including colorectal carcinoma (CRC).

To characterize the clinicopathologic features of CRC patients with somatic mutations in FAT cadherin family members.

We analyzed 526 CRC cases from The Cancer Genome Atlas PanCancer Atlas dataset. CRC samples were subclassified into 2 groups based on the presence or absence of somatic mutations in FAT1, FAT2, FAT3 and FAT4. Individual clinicopathological data were collected after digital slide review. Statistical analysis was performed using t tests and chi-square tests.

This CRC study cohort had frequent mutations in the FAT1 (10.5%), FAT2 (11.2%), FAT3 (15.4%) and FAT4 (23.4%) genes. Two hundred CRC patients (38.0%) harbored somatic mutations in one or more of the FAT family genes and were grouped into the FAT mutated CRC subtype. The FAT-mutated CRC subtype was more commonly located on the right side of the colon (51.0%) than in the rest of the cohort (30.1%, P < 0.001). It showed favorable clinicopathologic features, including a lower rate of positive lymph nodes (pN1-2: 33.5% vs 46.4%, P = 0.005), a lower rate of metastasis to another site or organ (pM1: 7.5% vs 16.3%, P = 0.006), and a trend toward an early tumor stage (pT1-2: 25.0% vs 18.7%, P = 0.093). FAT somatic mutations were significantly enriched in microsatellite instability CRC (28.0% vs 2.1%, P < 0.001). However, FAT somatic mutations in microsatellite stable CRC demonstrated similar clinicopathologic behaviors, as well as a trend of a better disease-free survival rate (hazard ratio = 0.539; 95% confidence interval: 0.301-0.967; log-rank P = 0.073).

FAT cadherin family genes are frequently mutated in CRC, and their mutation profile defines a subtype of CRC with favorable clinicopathologic characteristics.

FAT atypical cadherin 1 (FAT1) is among the most frequently mutated genes in many types of cancer. Its highest mutation rate is found in head and neck squamous cell carcinoma (HNSCC), in which FAT1 is the second most frequently mutated gene. Thus, FAT1 has great potential to serve as a target or prognostic biomarker in cancer treatment. FAT1 encodes a member of the cadherin-like protein family. Under normal physiological conditions, FAT1 serves as a molecular "brake" on mitochondrial respiration and acts as a receptor for a signaling pathway regulating cell-cell contact interaction and planar cell polarity. In many cancers, loss of FAT1 function promotes epithelial-mesenchymal transition (EMT) and the formation of cancer initiation/stem-like cells. However, in some types of cancer, overexpression of FAT1 leads to EMT. The roles of FAT1 in cancer progression, which seems to be cancer-type specific, have not been clarified. To further study the function of FAT1 in cancers, this review summarizes recent relevant literature regarding this protein. In addition to phenotypic alterations due to FAT1 mutations, several signaling pathways and tumor immune systems known or proposed to be regulated by this protein are presented. The potential impact of detecting or targeting FAT1 mutations on cancer treatment is also prospectively discussed.

Circular RNAs (circRNAs) belong to a novel class of noncoding RNA that gained more attention in human cancer pathogenesis. The role of circRNA in esophageal squamous cell carcinoma (ESCC) is largely unclear. Present investigation was to characterize new circRNAs regulating ESCC progression and explore the regulatory mechanisms in ESCC. In this study, circRNAs differentially expressed in ESCC and adjacent normal tissues were characterized via high-throughput sequencing. Then the differentially expressed circRNA between ESCC and adjacent normal tissues were investigated using Rt-qPCR. The role of circ-ARAP2 expression on tumor progression were detected in both in vivo and in vitro. Luciferase reporter assays were used to identify the relationships among circ-ARAP2, microRNA (miR)-761 and the cell cycle regulator Forkhead Box M1 (FOXM1). The result of the expression profile analyses regarding human circRNAs in ESCC demonstrated that circ-ARAP2 was up-regulated significantly in both ESCC tissues and cell lines. Downregulation circ-ARAP2 suppressed ESCC proliferation, tumor growth and metastasis in both in vivo and in vitro. The data also suggested that miR-761 and FOXM1 were circ-ARAP2 downstream targets which were confirmed through luciferase reporter analysis. Overexpression of FOXM1 or inhibiting miR-761 restored ESCC cell proliferation and invasion ability after silencing circ-ARAP2. The study also found that circ-ARAP2 influenced the endothelial-mesenchymal transition (EMT) and cancer stem cells differently by regulating miR-761/FOXM1. In one word, the results demonstrated that abnormal circ-ARAP2 expression promoted ESCC progression by regulating miR-761/FOXM1 axis-mediated stemness and EMT.