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Introduction: Macranthoidin B is one of the primary and unique triterpenoid saponin metabolites from Lonicera macranthoides Hand. –Mazz, which is used to treat endometriosis (EMS) in traditional Chinese medicine. However, the effect of macranthoidin B remains unknown in EMS. This study aimed to elucidate the effect and mechanism of macranthoidin B in EMS. Methods: Using rat autograft EMS model, the volume of ectopic endothelium, the histopathology, serum E2 and PROG were evaluated after macranthoidin B's treatment. In primary endometriotic stromal and HEC1-B cells, the invasion and metastasis were assessed by scratch wound and Transwell tests. The epithelial-mesenchymal transition and COX-2/PGE2 pathway were examined in vivo and in vitro. Macranthoidin B were combined with LPS or celecoxib. Results: In a rat autograft EMS model, macranthoidin B suppressed ectopic lesion volume, improved histopathological morphology, and regulated serum estradiol (E2) and progesterone (PROG) levels. Additionally, macranthoidin B inhibited invasion and metastasis of primary endometriotic stromal cells and HEC1-B cells. Mechanistically, macranthoidin B suppressed COX-2/PGE2 pathway and epithelial-mesenchymal transition both in vivo and in vitro. LPS, the COX-2/PGE2 pathway activator, showed the promotion of epithelial-mesenchymal transition, invasion and metastasis. Macranthoidin B exhibited the antagonistic effects against LPS. Celecoxib, the COX-2/PGE2 pathway inhibitor, restrained the epithelial-mesenchymal transition, invasion and metastasis. This effect of celecoxib was enhanced by macranthoidin B. Discussion: Macranthoidin B prevents epithelial-mesenchymal transition through COX-2/PGE2 pathway in EMS. It will facilitate the macranthoidin B's development and broaden its potential application. [ABSTRACT FROM AUTHOR]

Uveal melanoma (UM) poses a significant lethality, with approximately 50% of those developing metastases surviving less than one year. In the progression of UM, vasculogenic mimicry (VM) induced by hypoxia plays a pivotal role, which also partially explains the resistance of UM to anti-angiogenic therapies. Nevertheless, the crucial molecular mechanisms underlying VM in the progression of UM remain unclear. We identified ubiquitin conjugating enzyme E2 G2 (UBE2G2) as a critical suppressor through transcriptomic sequencing and metastasis correlation screening. In UM, hypoxia-induced VM and metastasis are markedly exacerbated by UBE2G2 knockdown and significantly alleviated by its overexpression. Mechanistically, UBE2G2 directly binds to galectin 3 binding protein (LGALS3BP) and forms a complex with the E3 ubiquitin ligase tripartite motif containing 38 (TRIM38), facilitating ubiquitination-mediated degradation of LGALS3BP at the K104 residue. Furthermore, UBE2G2 inhibits oncogenic phenotypes by inactivating intracellular PI3K/AKT signaling and reprogramming the tumor microenvironment. Therefore, targeting intercellular and intracellular molecular mechanisms of the hypoxia–UBE2G2–LGALS3BP axis may contribute to developing various therapeutic strategies for UM. This study demonstrated that targeting both intercellular and intracellular molecular mechanisms of the hypoxia–UBE2G2–LGALS3BP axis may contribute to developing various therapeutic strategies for uveal melanoma. [Display omitted] [ABSTRACT FROM AUTHOR]

Uveal melanoma (UM) poses a significant lethality, with approximately 50% of those developing metastases surviving less than one year. In the progression of UM, vasculogenic mimicry (VM) induced by hypoxia plays a pivotal role, which also partially explains the resistance of UM to anti-angiogenic therapies. Nevertheless, the crucial molecular mechanisms underlying VM in the progression of UM remain unclear. We identified ubiquitin conjugating enzyme E2 G2 (UBE2G2) as a critical suppressor through transcriptomic sequencing and metastasis correlation screening. In UM, hypoxia-induced VM and metastasis are markedly exacerbated by UBE2G2 knockdown and significantly alleviated by its overexpression. Mechanistically, UBE2G2 directly binds to galectin 3 binding protein (LGALS3BP) and forms a complex with the E3 ubiquitin ligase tripartite motif containing 38 (TRIM38), facilitating ubiquitination-mediated degradation of LGALS3BP at the K104 residue. Furthermore, UBE2G2 inhibits oncogenic phenotypes by inactivating intracellular PI3K/AKT signaling and reprogramming the tumor microenvironment. Therefore, targeting intercellular and intracellular molecular mechanisms of the hypoxia–UBE2G2–LGALS3BP axis may contribute to developing various therapeutic strategies for UM.

Abstract Background Research has elucidated that homeobox B9 (HOXB9), an important transcriptional activator, plays a pivotal role in promoting the invasion and metastasis of hepatocellular carcinoma (HCC) cells. However, the mechanism by which HOXB9 promotes the invasion and metastasis of HCC cells is incompletely understood and needs further exploration. Methods HOXB9 and snail family transcriptional repressor 2 (SNAI2) expression were analyzed using qRT-PCR and western blotting. The invasion and metastasis of hepatocellular carcinoma (HCC) cells were investigated using in vitro and in vivo assays. The H3K27me3 enrichment and HOXB9 interaction with microRNA 203a (MIR203A) or SNAI2 were detected using ChIP-qPCR. Transcriptional activities of SNAI2 and MIR203A promoter were detected using dual-luciferase reporter assays. Co-IP and GST pull-down assays were performed to confirm the binding between HOXB9 and EZH2. Results HOXB9 and SNAI2 were highly expressed in HCC tissues and their expression was positively intercorrelated and associated with poor prognosis in patients with HCC. In vitro and in vivo experiments confirmed that HOXB9 can upregulate the expression of SNAI2 to promote the invasion and metastasis of HCC cells. Furthermore, HOXB9 elevated SNAI2 expression by inhibiting MIR203A expression, a tumor suppressor gene, in HCC cells. Mechanistically, HOXB9 recruited enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) through interaction with its WD-binding domain, which increased EZH2-mediated histone H3 lysine 27 trimethylation (H3K27me3) at the MIR203A promoter region, in turn repressing the transcriptional activity and expression of MIR203A and consequently increasing the SNAI2 level in HCC cells. Finally, empirical evidence from in vitro and in vivo studies confirmed that mitigation of the HOXB9-mediated enhancement of epigenetic silencing of MIR203A inhibited SNAI2 expression, impeding the invasion and metastasis of HCC cells. Conclusions Our study reveals a novel mechanism by which HOXB9 promotes the invasion and metastasis of HCC cells and expands the understanding of the function of HOXB9 in tumor progression and provides a novel therapeutic strategy for curtailing HCC invasion and metastasis.

Background: The role of long non-coding RNAs (lncRNAs) in the invasion and metastasis of gastric cancer remains largely unclear. Methods: Integrating transcriptome data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, differentially expressed genes were identified in gastric cancer. Using the Catalogue of Somatic Mutations in Cancer (COSMIC) database-curated gene set, lncRNAs associated with invasion and metastasis were identified. The Cox analyses were performed to identify prognostic lncRNAs. The competing endogenous RNA (ceRNA) regulation network was constructed to identify hub lncRNAs in gastric cancer. Functional and pathway analyses were used to investigate the function of identified lncRNAs. RT-qPCR and Transwell assays were used to investigate the expression in gastric cancer tissues and functions in gastric cancer cell lines. Results: Based on GEO and TCGA databases, 111 differentially expressed lncRNAs were identified between gastric cancer and normal samples. A total of 43 lncRNAs were significantly correlated with hallmark genes of cancer invasion and metastasis. Among them, as a hub lncRNA in the invasion-related ceRNA regulation network, FAM87A showed potential regulation on MAPK signaling and transforming growth factor (TGF) signaling cascade, such as TGFB2, TGFBR1, and TGFBR2. Furthermore, FAM87A also showed a significant correlation with cell adhesion molecules, such as Integrin alpha 6 (ITGA6) and Contactin-1 (CNTN1). RT-qPCR experiments showed that FAM87A expression was upregulated in gastric cancer tissues compared to normal samples (n = 30). Transwell assays showed that FAM87A knockdown inhibited the migration and invasion abilities of gastric cancer cells in vitro. Notably, clinical data analysis showed that lncRNA FAM87A could be an independent factor for the overall survival of patients with gastric cancer. Conclusion: LncRNA FAM87A may play a pivotal role in regulating migration and invasion of gastric cancer cells. FAM87A could be a potential biomarker for the overall survival of patients with gastric cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Epithelial-to-mesenchymal transition (EMT) plays a critical role in cancer progression, contributing to the invasive and migratory abilities of tumor cells. In this study, we show that FBXO11 promotes the degradation of ZEB1, a key EMT regulator, via ubiquitination. Loss of FBXO11 increases ZEB1 levels, enhancing the invasiveness of lung cancer cells, while its overexpression reduces ZEB1 and suppresses invasion. Importantly, higher FBXO11 expression is associated with better prognosis in non-small cell lung cancer (NSCLC), highlighting its potential role as a therapeutic target for controlling EMT and cancer metastasis. Epithelial-to-mesenchymal transition (EMT) affects the invasion and migration of cancer cells. Here, we show that FBXO11 recognizes and promotes ubiquitin-mediated degradation of ZEB1. There is a strong association between FBXO11 and ZEB1 in non-small cell lung cancer (NSLC) in a clinical database. FBXO11 interacts with ZEB1, a core inducer of EMT. FBXO11 leads to increased ubiquitination and proteasomal degradation of ZEB1. Depletion of endogenous FBXO11 causes ZEB1 protein accumulation and EMT in A549 and H1299 cells, while overexpression of FBXO11 reduces ZEB1 protein abundance and cellular invasiveness. Importantly, the depletion of ZEB1 suppresses the increased migration and invasion of A549 and H1299 cells promoted by the depletion of FBXO11. The same results are shown in xenograft tumors. High FBXO11 expression is associated with a favorable prognosis in NSLC. Collectively, our study demonstrates that FBXO11 modulates EMT by mediating the stability of ZEB1 in lung cancer cells. [ABSTRACT FROM AUTHOR]

IntroductionMacranthoidin B is one of the primary and unique triterpenoid saponin metabolites from Lonicera macranthoides Hand. –Mazz, which is used to treat endometriosis (EMS) in traditional Chinese medicine. However, the effect of macranthoidin B remains unknown in EMS. This study aimed to elucidate the effect and mechanism of macranthoidin B in EMS.MethodsUsing rat autograft EMS model, the volume of ectopic endothelium, the histopathology, serum E2 and PROG were evaluated after macranthoidin B’s treatment. In primary endometriotic stromal and HEC1-B cells, the invasion and metastasis were assessed by scratch wound and Transwell tests. The epithelial-mesenchymal transition and COX-2/PGE2 pathway were examined in vivo and in vitro. Macranthoidin B were combined with LPS or celecoxib.ResultsIn a rat autograft EMS model, macranthoidin B suppressed ectopic lesion volume, improved histopathological morphology, and regulated serum estradiol (E2) and progesterone (PROG) levels. Additionally, macranthoidin B inhibited invasion and metastasis of primary endometriotic stromal cells and HEC1-B cells. Mechanistically, macranthoidin B suppressed COX-2/PGE2 pathway and epithelial-mesenchymal transition both in vivo and in vitro. LPS, the COX-2/PGE2 pathway activator, showed the promotion of epithelial-mesenchymal transition, invasion and metastasis. Macranthoidin B exhibited the antagonistic effects against LPS. Celecoxib, the COX-2/PGE2 pathway inhibitor, restrained the epithelial-mesenchymal transition, invasion and metastasis. This effect of celecoxib was enhanced by macranthoidin B.Discussion Macranthoidin B prevents epithelial-mesenchymal transition through COX-2/PGE2 pathway in EMS. It will facilitate the macranthoidin B’s development and broaden its potential application.

Abstract Mitochondria, responsible for cellular energy synthesis and signal transduction, intricately regulate diverse metabolic processes, mediating fundamental biological phenomena such as cell growth, aging, and apoptosis. Tumor invasion and metastasis, key characteristics of malignancies, significantly impact patient prognosis. Tumor cells frequently exhibit metabolic abnormalities in mitochondria, including alterations in metabolic dynamics and changes in the expression of relevant metabolic genes and associated signal transduction pathways. Recent investigations unveil further insights into mitochondrial metabolic abnormalities, revealing their active involvement in tumor cell proliferation, resistance to chemotherapy, and a crucial role in tumor cell invasion and metastasis. This paper comprehensively outlines the latest research advancements in mitochondrial structure and metabolic function. Emphasis is placed on summarizing the role of mitochondrial metabolic abnormalities in tumor invasion and metastasis, including alterations in the mitochondrial genome (mutations), activation of mitochondrial-to-nuclear signaling, and dynamics within the mitochondria, all intricately linked to the processes of tumor invasion and metastasis. In conclusion, the paper discusses unresolved scientific questions in this field, aiming to provide a theoretical foundation and novel perspectives for developing innovative strategies targeting tumor invasion and metastasis based on mitochondrial biology. Graphical Abstract

Abstract Zinc finger MIZ-type containing 1 (ZMIZ1) is a transcriptional coactivator related to the protein inhibitors of activated STATs (PIAS) family. Mounting evidence suggests that ZMIZ1 plays a crucial role in the occurrence and development of cancers. The function of ZMIZ1 in tongue squamous cell carcinoma (TSCC) and the mechanisms underpinning its role in this disease have not been fully clarified. We performed qualitative ZMIZ1 protein expression analyses using immunohistochemistry in 20 patient-derived, paraffin-embedded TSCC tissue sections. We used RNAi to knock down ZMIZ1 expression in the CAL-27 TSCC cell line and quantified the impact of ZMIZ1 knock down on proliferation, migration and apoptosis via CCK-8, scratch assay and flow cytometry, respectively. We used qRT-PCR and western blotting to investigate the role of ZMIZ1 in this cell line. Finally, we established a model of lung metastasis in nude mice to replicate the in vitro results. ZMIZ1 protein was significantly more abundant in TSCC case tissue samples. ZMIZ1 knockdown reduced the invasion and metastases of TSCC tumor cells and promoted apoptosis. ZMIZ1 knockdown was associated with the down-regulation of Notch signaling pathway related factors Jagged1 and Notch1, and invasion and metastasis related factors MKP-1, SSBP2 and MMP7 in vitro and in vivo, at the mRNA level. In vitro and in vivo data suggest that knock down of ZMIZ1 may inhibit TSCC invasion and metastasis by modulating Notch signaling. ZMIZ1 inhibition may therefore represent a new therapeutic target for TSCC.

AbstractThis study aims to explore the mechanisms of the inhibitory effect of kaempferol on the invasion and metastasis of gastric cancer (GC) cells through network pharmacology prediction and experimental verification. It identifies core targets via PPI network analysis and finds that kaempferol binds to these targets well. In vitro experiments showed that kaempferol could inhibit the proliferation, colony formation, migration and invasion of GC cells. Western blotting indicated kaempferol may reduce AKT and GSK3β phosphorylation, leading to lower expression of invasion-related genes SRC, MMP9, CXCR4, KDR, and MMP2. Overall, kaempferol may prevent migration and invasion of GC cells via the AKT/GSK3β signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Lung cancer remains the foremost reason of cancer‐related mortality, with invasion and metastasis profoundly influencing patient prognosis. N‐acetyltransferase 10 (NAT10) catalyzes the exclusive N (4)‐acetylcytidine (ac4C) modification in eukaryotic RNA. NAT10 dysregulation is linked to various diseases, yet its role in non‐small cell lung cancer (NSCLC) invasion and metastasis remains unclear. Our study delves into the clinical significance and functional aspects of NAT10 in NSCLC. Methods: We investigated NAT10's clinical relevance using The Cancer Genome Atlas (TCGA) and a group of 98 NSCLC patients. Employing WB, qRT‐PCR, and IHC analyses, we assessed NAT10 expression in NSCLC tissues, bronchial epithelial cells (BECs), NSCLC cell lines, and mouse xenografts. Further, knockdown and overexpression techniques (siRNA, shRNA, and plasmid) were employed to evaluate NAT10's effects. A series of assays were carried out, including CCK‐8, colony formation, wound healing, and transwell assays, to elucidate NAT10's role in proliferation, invasion, and metastasis. Additionally, we utilized lung cancer patient‐derived 3D organoids, mouse xenograft models, and Remodelin (NAT10 inhibitor) to corroborate these findings. Results: Our investigations revealed high NAT10 expression in NSCLC tissues, cell lines and mouse xenograft models. High NAT10 level correlated with advanced T stage, lymph node metastasis and poor overall survive. NAT10 knockdown curtailed proliferation, invasion, and migration, whereas NAT10 overexpression yielded contrary effects. Furthermore, diminished NAT10 levels correlated with increased E‐cadherin level whereas decreased N‐cadherin and vimentin expressions, while heightened NAT10 expression displayed contrasting results. Notably, Remodelin efficiently attenuated NSCLC proliferation, invasion, and migration by inhibiting NAT10 through the epithelial‐mesenchymal transition (EMT) pathway. Conclusions: Our data underscore NAT10 as a potential therapeutic target for NSCLC, presenting avenues for targeted intervention against lung cancer through NAT10 inhibition. [ABSTRACT FROM AUTHOR]

Interleukin-6 (IL-6) and hypoxia-inducible factor-1α (HIF-1α) play important roles in epithelial-mesenchymal transformation (EMT) and tumor development. Previous studies have demonstrated that IL-6 promotes EMT, invasion, and metastasis in epithelial ovarian cancer (EOC) cells by activating the STAT3/HIF-1α pathway. MicroRNA (miRNA) is non-coding small RNAs that also play an important role in tumor development. Notably, Let-7 and miR-200 families are prominently altered in EOC. However, whether IL-6 regulates the expression of Let-7 and miR-200 families through the STAT3/HIF-1α signaling to induce EMT in EOC remains poorly understood. In this study, we conducted in vitro and in vivo investigations using two EOC cell lines, SKOV3, and OVCAR3 cells. Our findings demonstrate that IL-6 down-regulates the mRNA levels of Let-7c and miR-200c while up-regulating their target genes HMGA2 and ZEB1 through the STAT3/HIF-1α signaling in EOC cells and in vivo. Additionally, to explore the regulatory role of HIF-1α on miRNAs, both exogenous HIF blockers YC-1 and endogenous high expression or inhibition of HIF-1α can be utilized. Both approaches can confirm that the downstream molecule HIF-1α inhibits the expression and function of Let-7c and miR-200c. Further mechanistic research revealed that the overexpression of Let-7c or miR-200c can reverse the malignant evolution of EOC cells induced by IL-6, including EMT, invasion, and metastasis. Consequently, our results suggest that IL-6 regulates the expression of Let-7c and miR-200c through the STAT3/HIF-1α pathway, thereby promoting EMT, invasion, and metastasis in EOC cells. [ABSTRACT FROM AUTHOR]

Epithelial-mesenchymal transition (EMT) has been implicated in various aspects of tumor development, including tumor invasion and metastasis, cancer stemness, and therapy resistance. Diverse stroma cell types along with biochemical and biophysical factors in the tumor microenvironment impinge on the EMT program to impact tumor progression. Here we provide an in-depth review of various tumor microenvironmental signals that regulate EMT in cancer. We discuss the molecular mechanisms underlying the role of EMT in therapy resistance and highlight new therapeutic approaches targeting the tumor microenvironment to impact EMT and tumor progression.

HMGA2, a pivotal transcription factor, functions as a versatile regulator implicated in the progression of diverse aggressive malignancies. In this study, mass spectrometry was employed to identify ubiquitin-specific proteases that potentially interact with HMGA2, and USP48 was identified as a deubiquitinating enzyme of HMGA2. The enforced expression of USP48 significantly increased HMGA2 protein levels by inhibiting its degradation, while the deprivation of USP48 promoted HMGA2 degradation, thereby suppressing tumor invasion and metastasis. We discovered that USP48 undergoes SUMOylation at lysine 258, which enhances its binding affinity to HMGA2. Through subsequent phenotypic screening of small molecules, we identified DUB-IN-2 as a remarkably potent pharmacological inhibitor of USP48. Interestingly, the small-molecule inhibitor targeting USP48 induces destabilization of HMGA2. Clinically, upregulation of USP48 or HMGA2 in cancerous tissues is indicative of poor prognosis for patients with colorectal cancer (CRC). Collectively, our study not only elucidates the regulatory mechanism of DUBs involved in HMGA2 stability and validates USP48 as a potential therapeutic target for CRC, but also identifies DUB-IN-2 as a potent inhibitor of USP48 and a promising candidate for CRC treatment.

Traditional Chinese medicine (TCM) has been used to treat triple-negative breast cancer (TNBC), a breast cancer subtype with poor prognosis. Clinical studies have verified that the Sanyingfang formula (SYF), a TCM prescription, has obvious effects on inhibiting breast cancer recurrence and metastasis, prolonging patient survival, and reducing clinical symptoms. However, its active ingredients and molecular mechanisms are still unclear. In this study, the active ingredients of each herbal medicine composing SYF and their target proteins are obtained from the Traditional Chinese Medicine Systems Pharmacology database. Breast cancer-related genes are obtained from the GeneCards database. Major targets and pathways related to SYF treatment in breast cancer are identified by analyzing the above data. By conducting molecular docking analysis, we find that the active ingredients quercetin and luteolin bind well to the key targets KDR1, PPARG, SOD1, and VCAM1. In vitro experiments verify that SYF can reduce the proliferation, migration, and invasion ability of TNBC cells. Using a TNBC xenograft mouse model, we show that SYF could delay tumor growth and effectively inhibit the occurrence of breast cancer lung metastasis in vivo. PPARG, SOD1, KDR1, and VCAM1 are all regulated by SYF and may play important roles in SYF-mediated inhibition of TNBC recurrence and metastasis.

Globally, breast cancer stands as the most prevalent form of cancer among women. The tumor microenvironment of breast cancer often exhibits hypoxia. Hypoxia-inducible factor 1-alpha, a transcription factor, is found to be overexpressed and activated in breast cancer, playing a pivotal role in the anoxic microenvironment by mediating a series of reactions. Hypoxiainducible factor 1-alpha is involved in regulating downstream pathways and target genes, which are crucial in hypoxic conditions, including glycolysis, angiogenesis, and metastasis. These processes significantly contribute to breast cancer progression by managing cancer-related activities linked to tumor invasion, metastasis, immune evasion, and drug resistance, resulting in poor prognosis for patients. Consequently, there is a significant interest in Hypoxia-inducible factor 1-alpha as a potential target for cancer therapy. Presently, research on drugs targeting Hypoxia-inducible factor 1-alpha is predominantly in the preclinical phase, highlighting the need for an in-depth understanding of HIF-1α and its regulatory pathway. It is anticipated that the future will see the introduction of effective HIF-1α inhibitors into clinical trials, offering new hope for breast cancer patients. Therefore, this review focuses on the structure and function of HIF-1α, its role in advancing breast cancer, and strategies to combat HIF-1α-dependent drug resistance, underlining its therapeutic potential. [ABSTRACT FROM AUTHOR]

Adhesion molecules mediate cell-to-cell and cell-to-extracellular matrix interactions and transmit mechanical and chemical signals among them. Various mechanisms deregulate adhesion molecules in cancer, enabling tumor cells to proliferate without restraint, invade through tissue boundaries, escape from immune surveillance, and survive in the tumor microenvironment. Recent studies have revealed that adhesion molecules also drive angiogenesis, reshape metabolism, and are involved in stem cell self-renewal. In this review, we summarize the functions and mechanisms of adhesion molecules in cancer and the tumor microenvironment, as well as the therapeutic strategies targeting adhesion molecules. These studies have implications for furthering our understanding of adhesion molecules in cancer and providing a paradigm for exploring novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) play important roles in cancer occurrence and progression. To explore and elucidate the clinical significance of specific circular RNA in melanoma and its potential molecular mechanism. CircROR1 expression in melanoma cells and tissues was confirmed by qRT–PCR and ISH. qRT–PCR and Western blotting were performed to measure the levels of CCNE1, KAT2A, MMP9 and TIMP2. MTT, Transwell and wound healing assays were performed to evaluate cell proliferation, invasion and metastasis. A xenograft mouse model was established to further verify the CircROR1/CCNE1 axis in vivo. RNA pull‐down and RIP assays were performed to detect the direct interaction KAT2A and CircROR1. A ChIP assay was used to investigate the enrichment of H3K9ac acetylation in the CCNE1 promoter. CircROR1 was significantly upregulated in metastatic melanoma cells and tissues, promoting proliferation, invasion and metastasis in vitro and tumour growth in vivo. CircROR1 overexpression increased CCNE1 and MMP9 protein expression and decreased TIMP2 protein expression. Functional rescue assays demonstrated that CircROR1 played a role in promoting malignant progression through CCNE1. CircROR1 specifically bound to the KAT2A protein without affecting its expression. CircROR1 overexpression increased the level of H3K9ac modification in the CCNE1 promoter region by recruiting KAT2A, thus upregulating CCNE1 expression. CircROR1 upregulates CCNE1 expression through KAT2A‐mediated histone acetylation. Our research confirms the critical role of CircROR1 in melanoma invasion and metastasis, and CircROR1 could serve as a potential therapeutic target for melanoma treatment. [ABSTRACT FROM AUTHOR]

HMGA2, a pivotal transcription factor, functions as a versatile regulator implicated in the progression of diverse aggressive malignancies. In this study, mass spectrometry was employed to identify ubiquitin-specific proteases that potentially interact with HMGA2, and USP48 was identified as a deubiquitinating enzyme of HMGA2. The enforced expression of USP48 significantly increased HMGA2 protein levels by inhibiting its degradation, while the deprivation of USP48 promoted HMGA2 degradation, thereby suppressing tumor invasion and metastasis. We discovered that USP48 undergoes SUMOylation at lysine 258, which enhances its binding affinity to HMGA2. Through subsequent phenotypic screening of small molecules, we identified DUB-IN-2 as a remarkably potent pharmacological inhibitor of USP48. Interestingly, the small-molecule inhibitor targeting USP48 induces destabilization of HMGA2. Clinically, upregulation of USP48 or HMGA2 in cancerous tissues is indicative of poor prognosis for patients with colorectal cancer (CRC). Collectively, our study not only elucidates the regulatory mechanism of DUBs involved in HMGA2 stability and validates USP48 as a potential therapeutic target for CRC, but also identifies DUB-IN-2 as a potent inhibitor of USP48 and a promising candidate for CRC treatment. This study not only elucidates the regulatory mechanism of USP48 involved in HMGA2 stability, but also identifies DUB-IN-2 as a potent inhibitor of USP48 and a promising candidate for CRC treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Background Fringe is a glycosyltransferase involved in tumor occurrence and metastasis. However, a comprehensive analysis of the Fringe family members lunatic fringe (LFNG), manic fringe (MFNG), radical fringe (RFNG) in human cancers is lacking. Methods In this study, we performed a pan-cancer analysis of Fringe family members in 33 cancer types with transcriptomic, genomic, methylation data from The Cancer Genome Atlas (TCGA) project. The correlation between Fringe family member expression and patient overall survival, copy number variation, methylation, Gene Ontology enrichment, and tumor-infiltrating lymphocytes (TILs) was investigated by using multiple databases, such as cBioPortal, Human Protein Atlas, GeneCards, STRING, MSigDB, TISIDB, and TIMER2. In vitro experiments and immunohistochemical assays were performed to validate our findings. Results High expression levels of LFNG, MFNG, RFNG were closely associated with poor overall survival in multiple cancers, particularly in pancreatic adenocarcinoma (PAAD), uveal melanoma (UVM), and brain lower-grade glioma (LGG). Copy number variation analysis revealed that diploid and gain mutations of LFNG was significantly increased in PAAD and stomach adenocarcinoma (STAD), and significantly associated with the methylation levels in promoter regions. Significant differential genes between high and low expression groups of these Fringe family members were found to be consistently enriched in immune response and T cell activation pathway, extracellular matrix adhesion pathway, RNA splicing and ion transport pathways. Correlation between the abundance of tumor-infiltrating lymphocytes (TILs) and LFNG, MFNG, and RFNG expression showed that high LFNG expression was associated with lower TIL levels, particularly in PAAD. In vitro experiment by using pancreatic cancer PANC1 cells showed that LFNG overexpression promoted cell proliferation and invasion. Immunohistochemical assay in 90 PAAD patients verified the expression level of LFNG and its relationship with the prognosis. Conclusions Our study provides a relatively comprehensive understanding of the expression, mutation, copy number, promoter methylation level changes along with prognosis values of LFNG, MFNG, and RFNG in different tumors. High LFNG expression may serve as a poor prognosis molecular marker for PAAD.

Acting as a cysteine protease, small ubiquitin-like modifier (SUMO)/sentrinspecific protease1 (SENP1) involved in multiple physiological and pathological processes through processing the precursor SUMO protein into mature form and deSUMOylating target protein. It has been reported that SENP1 is highly expressed and plays a carcinogenic role in various cancers. In this paper, we mainly explore the function and mechanism of SENP1 in tumor cell proliferation, apoptosis, invasion, metastasis, stemness, angiogenesis, metabolism and drug resistance. Furthermore, the research progress of SENP1 inhibitors for cancer treatment is introduced. This study aims to provide theoretical references for cancer therapy by targeting SENP1. [ABSTRACT FROM AUTHOR]

Tumor microenvironment (TME) of solid tumors including breast cancer is complex and contains a distinct cytokine pattern including TNF-α, which determines the progression and metastasis of breast tumors. The metastatic potential of triple negative breast cancer subtypes is high as compared to other subtypes of breast cancer. NF-κB is key transcription factor regulating inflammation and mitochondrial bioenergetics including oxidative phosphorylation (OXPHOS) genes which determine its oxidative capacity and generating reducing equivalents for synthesis of key metabolites for proliferating breast cancer cells. The differential metabolic adaptation and OXPHOS function of breast cancer subtypes in inflammatory conditions and its contribution to metastasis is not well understood. Here we demonstrated that different subunits of NF-κB are differentially expressed in subtypes of breast cancer patients. RELA, one of the major subunits in regulation of the NF-κB pathway is positively correlated with high level of TNF-α in breast cancer patients. TNF-α induced NF-κB regulates the expression of LYRM7, an assembly factor for mitochondrial complex III. Downregulation of LYRM7 in MDA-MB-231 cells decreases mitochondrial super complex assembly and enhances ROS levels, which increases the invasion and migration potential of these cells. Further, in vivo studies using Infliximab, a monoclonal antibody against TNF-α showed decreased expression of LYRM7 in tumor tissue. Large scale breast cancer databases and human patient samples revealed that LYRM7 levels decreased in triple negative breast cancer patients compared to other subtypes and is determinant of survival outcome in patients. Our results indicate that TNF-α induced NF-κB is a critical regulator of LYRM7, a major factor for modulating mitochondrial functions under inflammatory conditions, which determines growth and survival of breast cancer cells. [Display omitted] • RELA positively correlates with TNF-α level in breast cancer patients. • TNF-α induced NF-κB regulates the expression of LYRM7. • LYRM7 knockdown regulates mitochondrial super complex assembly and ROS levels. • Infliximab, mAb against TNF-α showed decreased expression of LYRM7 in tumor tissue in vivo. • LYRM7 decreased in triple negative breast cancer patients and is determinant of survival outcome. [ABSTRACT FROM AUTHOR]

Purpose: Studies have shown that circRNA is involved in the occurrence and development of human cancers. However, it remains unclear that the contribution of circRNA in thyroid carcinoma and its role in the process of tumorigenesis. Methods: The expression profile of circRNA-miRNA-mRNA in thyroid carcinoma was detected by RNA sequencing and verified by qRT-PCR. The characteristics of circGLIS3 were verified by RNase R and actinomycin assays, subcellular fractionation, and fluorescence in situ hybridization. The functions of circGLIS3 and AIF1L were detected by wound healing, transwell, 3D culture and Western blot. RNA Immunoprecipitation (RIP), RNA pulldown and dual-luciferase reporter assays were used to verify the target genes of circGLIS3 and downstream miRNAs. Functional rescue experiments were performed by transfecting miRNA mimics or siRNA of target genes. Finally, metastatic mouse models were used to investigate circGLIS3 function in vivo. Results: In this study, we discovered a novel circRNA (has_circ_0007368, named as circGLIS3) by RNA sequencing. CircGLIS3 was down-regulated in thyroid carcinoma tissues and cells line, and was negatively associated with malignant clinical features of thyroid carcinoma. Functional studies found that circGLIS3 could inhibit the migration and invasion of thyroid carcinoma cells, and was related to the EMT process. Mechanistically, circGLIS3 can upregulate the expression of the AIF1L gene by acting as a miR-146b-3p sponge to inhibit the progression of thyroid carcinoma. Conclusion: Our study identified circGLIS3 as a novel tumor suppressor in thyroid cancer, indicating the potential of circGLIS3 as a promising diagnostic and prognostic marker for thyroid cancer. [ABSTRACT FROM AUTHOR]

Background: MicroRNAs and traditional Chinese medicine have emerged as pivotal regulators in the progression of gastric carcinoma. Huashi Jiedu decoction has been clinically used to enhance the quality of life in gastric carcinoma patients. Therefore, the present study aimed to elucidate the involvement of MicroRNAs and Huashi Jiedu decoction in gastric carcinoma metastasis and investigate their regulatory mechanisms in anti-tumor effects. Methods: Subsequently, the effect of Huashi Jiedu decoction on gastric carcinoma cell metastasis and proliferation was verified using cell counting kit-8, flow cytometry, wounding healing, and Transwell assays. LncRNA-p21 knockdown cells were successfully established in BGC-823 and MGC-803 cell lines. Mouse models inoculated with MGC-803 cells were generated, and the cellular morphology in tissues was assessed using hematoxylin staining. Additionally, western blot and immunohistochemistry analysis were performed to evaluate the expression of epithelial-mesenchymal transition-related proteins, with real-time PCR validation conducted in both in vitro and in vivo settings. Results: Network pharmacology revealed a close association between proteins involved in the epithelial-mesenchymal transition process and LncRNA-p21 in gastric carcinoma, consistent with the downregulated expression of E-cadherin, N-cadherin, and Twist following LncRNA-p21 knockdown. Cell counting kit-8 and flow cytometry assays confirmed that Huashi Jiedu decoction exhibited concentration-dependent cytotoxicity, effectively inhibiting the distant metastasis of gastric carcinoma cells in wound healing and invasion experiments. Treatment with Huashi Jiedu decoction resulted in increased expression of E-cadherin, N-cadherin, and LncRNA-p21 in both in vitro and in vivo models, as validated by western blot, real-time PCR, and immunohistochemistry. Conclusion: Collectively, our findings demonstrate that Huashi Jiedu decoction suppresses epithelial-mesenchymal transition and inhibits gastric carcinoma invasion and metastasis both in vivo and in vitro through the knockdown of LncRNA-p21, corroborating the initial findings from our network pharmacology analysis. [ABSTRACT FROM AUTHOR]

Pseudogenes were initially thought to have no function and were called by aliases, such as "junk genes." With the emergence of large-scale genomics projects and more and more experimental studies, pseudogenes have been shown to play an important role in the occurrence and development of solid tumors, especially playing an important regulatory role in the occurrence and develepment of liver cancer, such as regulating the proliferation, apoptosis, invasion, metastasis, and immunity of liver cancer cells. Recent studies showed that pseudogenes can act as regulators of oncogenes and tumor suppressors in hepatocellular carcinoma (HCC) and can thus serve as prognostic markers and even therapeutic targets for this cancer type. In this review, we systematically summarize the mechanisms and functions of different pseudogenes in HCC and present their future prospects as therapeutic targets.

Abstract Papillary thyroid carcinoma (PTC) is one of the most common thyroid carcinomas. The gross extrathyroidal extension and extensive metastases of PTC lead to high rates of recurrence and poor clinical outcomes. However, the mechanisms underlying PTC development are poorly understood. In this study, using single-cell RNA sequencing, the transcriptome profiles of two PTC patients were addressed, including PTC1 with low malignancy and good prognosis and PTC2 with high malignancy and poor prognosis. We found that epithelial subcluster Epi02 was the most associated with the malignant development of PTC cells, with which the fold change of Chitinase 3-like 1 (CHI3L1) is on the top of the differentially expressed genes between PTC1 and PTC2 (P

Objective To investigate the expression level of RING finger protein 187 （RNF187） and its effect on the proliferation and invasion of prostate cancer （PCa） cells. Methods The differences in the expression of RNF187 between PCa and normal tissues was mined through TCGA and GEO databases. Normal prostate epithelial cell line RWPE-1， and human PCa cell lines LNCaP， C4-2， DU145 and PC-3 cell lines were cultured in vitro. The expression levels of RNF187 mRNA in RWPE-1， LNCaP， C4-2， DU145 and PC-3 were determined by quantitative fluorescent real-time PCR （RT-qPCR）. The expression level of RNF187 protein was determined by Western blot. DU145， PC-3 cells were transfected with RNF187-siRNA1 and RNF187-siRNA2. The relative expression level of RNF187 mRNA was determined by RT-qPCR. Cell viability was detected by CCK-8 assay. Cell proliferation was measured by 5-ethynyl-2´-deoxyuridine （EdU） labeling. Cell migration and invasion were measured by Transwell chamber. The expression levels of RNF187， epithelial-mesenchymal transition （EMT） marker proteins and matrix metalloproteinase-9 （MMP-9） were determined by Western blot. Results In TCGA and GEO datasets， the expression level of RNF187 in the PCa tissues was significantly up-regulated than that in the normal prostate tissues. Patients with higher Gleason scores and higher staging had higher expression levels of RNF187 （all P < 0.05）. The expression levels of RNF187 mRNA and protein in PC-3， LNCaP， C4-2 and DU145 cells were significantly up-regulated than those in RWPE-1 cells （all P < 0.01）. The relative expression levels of RNF187 mRNA in DU145 and PC-3 cells in the RNF187-si1 and RNF187-si2 groups were significantly down-regulated than those in the control group （all P < 0.001）. After RNF187 knock-down， the viability， proliferation， invasion and migration capabilities of DU145 and PC-3 cells were significantly decreased， the relative expression levels of RNF187， N-cadherin， Vimentin and MMP-9 proteins were significantly down-regulated， whereas the relative expression levels of E-cadherin were significantly up-regulated （all P < 0.05）. Conclusion RNF187 is over-expressed in PCa tissues. Knock-down of RNF187 can reduce the cell viability， proliferation， invasion and migration of DU145 and PC-3 cells.

Metastasis is the main cause of cancer-related death. Growing evidence has shown that changes in glucose metabolism in nasopharyngeal carcinoma cells affect the invasion and metastasis of nasopharyngeal carcinoma through many pathways. This review summarizes the molecular mechanism underlying abnormal glucose metabolism in nasopharyngeal carcinoma cells and analyzes its relationship with the invasion and metastasis of nasopharyngeal carcinoma, including aerobic glycolysis, aerobic oxidation, and pentose phosphate pathway. The aim is to provide novel approaches using the relationships among glucose metabolism, invasion, and metastasis in the targeted therapy of nasopharyngeal carcinoma.

The later stages of cancer, including the invasion and colonization of new tissues, are actively mysterious compared to earlier stages like primary tumor formation. While we lack many details about both, we do have an apparently successful explanatory framework for the earlier stages: one in which genetic mutations hold ultimate causal and explanatory power. By contrast, on both empirical and conceptual grounds, it is not currently clear thatmutations alone can explain the later stages of cancer. Can a different type of molecular change do better? Here, I introduce the "permissive binding theory" of cancer, which proposes that novel protein binding interactions are the key causal and explanatory entity in invasion and metastasis. It posits that binding is more abundant at baseline than we observe because it is restricted in normal physiology; that any large perturbation to physiological state revives this baseline abundance, unleashing many new binding interactions; and that a subset of these cause the cellular functions at the heart of oncogenesis, especially invasion and metastasis. Significant physiological perturbations occur in cancer cells in very early stages, and generally become more extreme with progression, providing interactions that continually fuel invasion and metastasis. The theory is compatible with, but not limited to, causal roles for the diverse molecular changes observed in cancer (e.g. gene expression or epigenetic changes), as these generally act causally upstream of proteins, and so may exert their effects by changing the protein binding interactions that occur in the cell. This admits the possibility that molecular changes that appear quite different may actually converge in creating the same few protein complexes, simplifying our picture of invasion and metastasis. If correct, the theory offers a concrete therapeutic strategy: targeting the key novel complexes. The theory is straightforwardly testable by large-scale identification of protein interactions in different cancers. [ABSTRACT FROM AUTHOR]

Background: Fringe is a glycosyltransferase involved in tumor occurrence and metastasis. However, a comprehensive analysis of the Fringe family members lunatic fringe (LFNG), manic fringe (MFNG), radical fringe (RFNG) in human cancers is lacking. Methods: In this study, we performed a pan-cancer analysis of Fringe family members in 33 cancer types with transcriptomic, genomic, methylation data from The Cancer Genome Atlas (TCGA) project. The correlation between Fringe family member expression and patient overall survival, copy number variation, methylation, Gene Ontology enrichment, and tumor-infiltrating lymphocytes (TILs) was investigated by using multiple databases, such as cBioPortal, Human Protein Atlas, GeneCards, STRING, MSigDB, TISIDB, and TIMER2. In vitro experiments and immunohistochemical assays were performed to validate our findings. Results: High expression levels of LFNG, MFNG, RFNG were closely associated with poor overall survival in multiple cancers, particularly in pancreatic adenocarcinoma (PAAD), uveal melanoma (UVM), and brain lower-grade glioma (LGG). Copy number variation analysis revealed that diploid and gain mutations of LFNG was significantly increased in PAAD and stomach adenocarcinoma (STAD), and significantly associated with the methylation levels in promoter regions. Significant differential genes between high and low expression groups of these Fringe family members were found to be consistently enriched in immune response and T cell activation pathway, extracellular matrix adhesion pathway, RNA splicing and ion transport pathways. Correlation between the abundance of tumor-infiltrating lymphocytes (TILs) and LFNG, MFNG, and RFNG expression showed that high LFNG expression was associated with lower TIL levels, particularly in PAAD. In vitro experiment by using pancreatic cancer PANC1 cells showed that LFNG overexpression promoted cell proliferation and invasion. Immunohistochemical assay in 90 PAAD patients verified the expression level of LFNG and its relationship with the prognosis. Conclusions: Our study provides a relatively comprehensive understanding of the expression, mutation, copy number, promoter methylation level changes along with prognosis values of LFNG, MFNG, and RFNG in different tumors. High LFNG expression may serve as a poor prognosis molecular marker for PAAD. [ABSTRACT FROM AUTHOR]

Recent research has indicated that Long noncoding RNAs (LncRNAs) are crucial in many disorders, especially tumors. However, the exact role of LncRNA XLOC_006786 (LncRNA-SPIDR-2:1) in malignancies, especially in human osteosarcoma, is unclear. The results of RT‒qPCR, western blotting, CCK-8 assays, and Transwell assays showed that LncRNA XLOC_006786 inhibited osteosarcoma cell proliferation, invasion, and migration, indicating that it may be a tumor suppressor gene in osteosarcoma. We found that LncRNA XLOC_006786 negatively regulated NOTCH3, which is an oncogenic gene in osteosarcoma, as we previously reported. Bioinformatics analysis showed that miR-491-5p may be a direct target of LncRNA XLOC_006786, while NOTCH3 is a key target of miR-491-5p. Then, we verified that LncRNA XLOC_006786 could prevent lung metastatic osteosarcoma in vivo. Taken together, our research showed that LncRNA XLOC_006786 suppresses osteosarcoma proliferation, invasion, and metastasis through the NOTCH3 signaling pathway by targeting miR-491-5p. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects and preliminary mechanisms of the extract CII-3 and defatted ointment of Periplaneta americana on autophagy, invasion and metastasis of drug-resistant hepatocellular carcinoma cell line BEL-7402/5-FU. Methods: The transplantation tumors of liver cancer-sensitive cells BEL7402 and liver cancer-resistant cells BEL-7402/5-FU were treated with Sorafenib, CII-3, and defatted ointment drugs. Then, the serum biochemical indicators of the nude mice, changes in tumor size, and changes in organ indices such as heart, liver, kidney, and spleen were observed after drug administration. The histopathological changes in the liver and tumor were also observed, along with changes in autophagy-related factors and invasion and metastasis-related factors in tumor tissue cells. Results: CII-3 and the deffated cream reduced the body weight of nude mice and inhibited tumor growth, significantly reducing tumor weight (P < 0.01). CII-3 increased the spleen index and heart index (P < 0.05)；compared to the drug-resistant group, the CII-3 group showed an upward trend in serum CR (P < 0.05). Sorafenib and CII-3 treatment induced tumor tissue necrosis, with better effects than the deffatede ointment group；compared to the drug-resistant group, both the CII-3 and deffatede ointment groups significantly inhibited autophagy and invasion-related factors, except for AKT (P < 0.05). Conclusion Periplaneta americana extract CII-3 and deffatede ointment can inhibit the autophagy, invasion and metastasis of drugresistant hepatocellular carcinoma cells, and also have a good anti-tumor effect. Further observation is needed for its liver and kidney damage on nude mice with hepatocellular carcinoma transplanted tumors. [ABSTRACT FROM AUTHOR]

Xialu Zhang,1,&ast; Chenguang Zhang,1,2,&ast; Qingfang Zhao,1 Shanshan Wang,3 Liyong Wang,4 Yang Si,1 Qiang Su,5 Shan Cheng,1 Wei Ding1 1School of Basic Medical Sciences, Capital Medical University, Beijing, People’s Republic of China; 2Beijing Key Laboratory for Cancer Invasion and Metastasis Mechanism Research, Capital Medical University, Beijing, People’s Republic of China; 3Beijing Institute of Hepatology, Beijing You’An Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Core Facilities for Molecular Biology, Capital Medical University, Beijing, People’s Republic of China; 5Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chenguang Zhang; Wei Ding, Email chzhang@ccmu.edu.cn; weiding@ccmu.edu.cnObjective: To investigate the involvement and transcriptional targets of zinc finger protein 281 (ZNF281) in the progression of hepatocellular carcinoma (HCC).Methods: The expression of ZNF281 in HCC was detected in tissue microarray and cell lines. The role of ZNF281 in aggressiveness of HCC was examined using wound healing, matrigel transwell, pulmonary metastasis model and assays for expression of EMT markers. RNA-seq was used to find potential target gene of ZNF281. Chromatin immunoprecipitation (ChIP) assay and co-immunoprecipitation (Co-IP) were employed to uncover the mechanism of the transcriptional regulation of ZNF281 on the target gene.Results: ZNF281 was increased in tumor tissues and positively correlated with vascular invasion in HCC. Knockdown of ZNF281 suppressed the migration and invasion with significant alteration of EMT marker expression in HLE and Huh7 HCC cell lines. RNA-seq screening showed that the tumor suppressor gene Annexin A10 (ANXA10) was a most up-regulated gene in response to ZNF281 depletion and responsible for the attenuation of aggressiveness. Mechanistically, ZNF281 interacted with the ANXA10 promoter region harboring ZNF281 recognition sites, and recruited components of nucleosome remodeling and deacetylation (NuRD) complex. By knocking down such components like HDAC1 or MTA1, ANXA10 was released from transcriptional repression by ZNF281/NuRD, and in turn reversed the EMT, invasion and metastasis driven by ZNF281.Conclusion: ZNF281 drives invasion and metastasis of HCC partially through transcriptional repression of tumor suppressor gene ANXA10 by recruiting NuRD complex.Graphical Abstract: Keywords: zinc finger protein 281, Annexin A10, nucleosome remodeling and deacetylation complex, hepatocellular carcinoma, invasion and metastasis, transcription

Abstract Background Previous studies have reported the role of circular RNAs (circRNAs) in the progression of non‐small‐cell lung cancer (NSCLC). SWT1‐derived circRNAs were confirmed to affect the apoptosis of cardiomyocytes; however, the biological functions of SWT1‐derived circRNAs in cancers are still unknown. Here, we investigated the potential role of SWT1‐derived circRNAs in NSCLC. Methods We used quantitative real‐time polymerase chain reaction (qRT‐PCR) to measure the expression of circSWT1 in NSCLC tissues and paired normal tissues. The potential functions of circSWT1 in tumor progression were assessed by CCK‐8, colony formation, wound healing, and matrigel transwell assays in vitro and by xenograft tumor models in vivo. Next, epithelial‐mesenchymal transition (EMT) was evaluated by western blotting, immunofluorescence, and immunohistochemistry (IHC). Moreover, circRIP, RNA pulldown assays, luciferase reporter gene assays, and FISH were conducted to illuminate the molecular mechanisms of circSWT1 via the miR‐370‐3p/SNAIL signal pathway. Then, we knocked out SNAIL in A549 and H1299 cells to identify the roles of circSWT1 in the progression and EMT of NSCLC through SNAIL. Finally, circSWT1 functions were confirmed in vivo using xenograft tumor models. Results CircSWT1 expression was significantly upregulated in NSCLC tissues, and high expression of circSWT1 predicted poor prognosis in NSCLC via survival analysis. In addition, overexpression of circSWT1 promoted the invasion and migration of NSCLC cells. Subsequently, we found that overexpression of circSWT1 induced EMT and that knockdown of circSWT1 inhibited EMT in NSCLC cells. Mechanistically, circSWT1 relieved the inhibition of downstream SNAIL by sponging miR‐370‐3p. Moreover, we found that these effects could be reversed by knocking out SNAIL. Finally, we verified that circSWT1 promoted NSCLC progression and EMT in xenograft tumor models. Conclusion CircSWT1 promoted the invasion, migration, and EMT of NSCLC. CircSWT1 could serve as a potential biomarker and a potential therapeutic target for NSCLC.

Abstract Background Breast cancer is the most common malignant tumor that threatens women's health. Attention has been paid on the study of long- non-coding RNA (lncRNA) in breast cancer. However, the specific mechanism remains not clear. Methods In this study, we explored the role of lncRNA BC069792 in breast cancer. In vitro and in vivo functional experiments were carried out in cell culture and mouse models. High-throughput next-generation sequencing technology and real-time fluorescence quantitative PCR technology were used to evaluate differentially expressed genes and mRNA expression, Western blot and immunohistochemical staining were used to detect protein expression. RNA immunoprecipitation assay and dual-luciferase activity assay were used to evaluate the competing endogenous RNAs (ceRNA), and rescue and mutation experiments were used for verification. Results We found that lncRNA BC069792 was expressed at a low level in breast cancer tissues, and significantly decreased in breast cancer with high pathological grade, lymph node metastasis and high Ki-67 index groups. Moreover, BC069792 inhibited the proliferation, invasion and metastasis of breast cancer cells in vitro and in vivo. Mechanically, BC069792 acts as a molecular sponge to adsorb hsa-miR-658 and hsa-miR-4739, to up-regulate the protein expression of Potassium Voltage-Gated Channel Q4 (KCNQ4), inhibits the activities of JAK2 and p-AKT, and plays a role in inhibiting breast cancer growth. Conclusions LncRNA BC069792 plays the role of tumor suppressor gene in breast cancer and is a new diagnostic index and therapeutic target in breast cancer.

Exosomes are a unique type of extracellular vesicles that contain a plethora of biological cargo such as miRNA, mRNA, long non-coding RNA, DNA, proteins and lipids. Exosomes serve as very effective means of intercellular communication. Due the presence of a lipid bilayer membrane, exosomes are resistant to degradation and are highly stable. This makes them easily identifiable in blood and other bodily fluids such as saliva. The exosomes that are secreted from a parent cell directly release their contents into the cytoplasm of a recipient cell and influence their cellular activity and function. Exosomes can also transfer their content between cancer cells and normal cells and regulate the tumor microenvironment. Exosomes play a vital role in tumor growth, tumor invasion and metastasis. Exosomes provide a multitude of molecular and genetic information and have become valuable indicators of disease activity at the cellular level. This review explores the molecular characteristics of exosomes and the role that exosomes play in the tumorigenesis pathway of potentially malignant oral lesions and head and neck cancers The application of exosomes in the treatment of oral cancers is also envisioned. Exosomes are very small and can easily pass through various biological barriers, making them very good delivery vectors for therapeutic drugs as well as to selectively induce DNA’s mRNA and miRNAs into targeted cancer cells.

Objective To explore the expression of miR-101-3p in gastric cancer and its mechanism on the invasion, metastasis, and angiogenesis of gastric cancer cells by targeting the STC-1 gene to regulate the PI3K/AKT signaling pathway. Methods qRT-PCR was used to detect the expression of miR-101-3p and STC-1 mRNA in gastric cancer tissues and BGC-823 cell and analyze the relationship between miR-101-3p expression and patients' clinical pathological factors. The cells were transfected with miRNA mimics and plasmids separately or in combination with LipofectamineTM 2000. TargetScanHuman prediction and dual-luciferase assay were used to verify the targeted regulation of miR-101-3p on STC-1. The effect and possible mechanism of miR-101-3p targeting the STC-1 gene on the invasion, metastasis, and angiogenesis of cancer cells were verified by scratch test, Transwell chamber test, Matrigel in vitro tube forming test, and Western blot assay. The development of the transplanted tumor was detected by nude mouse tumorigenicity test. Results The expression of STC-1 in gastric cancer tissues was higher than that in normal tissues. Compared with normal gastric tissues and GES-1 cells, miR-101-3p was down-regulated, and STC-1 mRNA was up-regulated in gastric cancer tissues and BGC-823 cell. The level of miR-101-3p was negatively correlated with the level of STC-1, and significantly correlated with the degree of tumor differentiation, TNM stage, and lymph node metastasis (P < 0.05). miR-101-3p directly targeted STC-1. The overexpression of miR-101-3p inhibited STC-1 expression and downregulated the expression of p-PI3K/PI3K, p-AKT/AKT, MMP-2, MMP-9, VEGF, and Ang2, consequently, inhibited tumor cell invasion, metastasis, and angiogenesis and reduced the size and weight of the transplanted tumors (P < 0.05). Conclusion miR-101-3p is down-regulated in gastric cancer and can target the STC-1 gene to regulate the PI3K/AKT signaling pathway and inhibit the invasion, metastasis, and angiogenesis of BGC-823 gastric cancer cells and the development of transplanted tumors in vivo.

The later stages of cancer, including the invasion and colonization of new tissues, are actively mysterious compared to earlier stages like primary tumor formation. While we lack many details about both, we do have an apparently successful explanatory framework for the earlier stages: one in which genetic mutations hold ultimate causal and explanatory power. By contrast, on both empirical and conceptual grounds, it is not currently clear that mutations alone can explain the later stages of cancer. Can a different type of molecular change do better? Here, I introduce the “permissive binding theory” of cancer, which proposes that novel protein binding interactions are the key causal and explanatory entity in invasion and metastasis. It posits that binding is more abundant at baseline than we observe because it is restricted in normal physiology; that any large perturbation to physiological state revives this baseline abundance, unleashing many new binding interactions; and that a subset of these cause the cellular functions at the heart of oncogenesis, especially invasion and metastasis. Significant physiological perturbations occur in cancer cells in very early stages, and generally become more extreme with progression, providing interactions that continually fuel invasion and metastasis. The theory is compatible with, but not limited to, causal roles for the diverse molecular changes observed in cancer (e.g. gene expression or epigenetic changes), as these generally act causally upstream of proteins, and so may exert their effects by changing the protein binding interactions that occur in the cell. This admits the possibility that molecular changes that appear quite different may actually converge in creating the same few protein complexes, simplifying our picture of invasion and metastasis. If correct, the theory offers a concrete therapeutic strategy: targeting the key novel complexes. The theory is straightforwardly testable by large-scale identification of protein interactions in different cancers.

Copyright of Cancer Research on Prevention & Treatment is the property of Cancer Research on Prevention & Treatment Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Exosomes are a unique type of extracellular vesicles that contain a plethora of biological cargo such as miRNA, mRNA, long non-coding RNA, DNA, proteins and lipids. Exosomes serve as very effective means of intercellular communication. Due the presence of a lipid bilayer membrane, exosomes are resistant to degradation and are highly stable. This makes them easily identifiable in blood and other bodily fluids such as saliva. The exosomes that are secreted from a parent cell directly release their contents into the cytoplasm of a recipient cell and influence their cellular activity and function. Exosomes can also transfer their content between cancer cells and normal cells and regulate the tumor microenvironment. Exosomes play a vital role in tumor growth, tumor invasion and metastasis. Exosomes provide a multitude of molecular and genetic information and have become valuable indicators of disease activity at the cellular level. This review explores the molecular characteristics of exosomes and the role that exosomes play in the tumorigenesis pathway of potentially malignant oral lesions and head and neck cancers The application of exosomes in the treatment of oral cancers is also envisioned. Exosomes are very small and can easily pass through various biological barriers, making them very good delivery vectors for therapeutic drugs as well as to selectively induce DNA’s mRNA and miRNAs into targeted cancer cells.

Papillary thyroid carcinoma (PTC) is one of the most common thyroid carcinomas. The gross extrathyroidal extension and extensive metastases of PTC lead to high rates of recurrence and poor clinical outcomes. However, the mechanisms underlying PTC development are poorly understood. In this study, using single-cell RNA sequencing, the transcriptome profiles of two PTC patients were addressed, including PTC1 with low malignancy and good prognosis and PTC2 with high malignancy and poor prognosis. We found that epithelial subcluster Epi02 was the most associated with the malignant development of PTC cells, with which the fold change of Chitinase 3-like 1 (CHI3L1) is on the top of the differentially expressed genes between PTC1 and PTC2 (P < 0.001). However CHI3L1 is rarely investigated in PTC as far. We then studied its role in PTC with a series of experiments. Firstly, qRT-PCR analysis of 14 PTC patients showed that the expression of CHI3L1 was positively correlated with malignancy. In addition, overexpression or silencing of CHI3L1 in TPC-1 cells, a PTC cell line, cultured in vitro showed that the proliferation, invasion, and metastasis of the cells were promoted or alleviated by CHI3L1. Further, immunohistochemistry analysis of 110 PTC cases revealed a significant relationship between CHI3L1 protein expression and PTC progression, especially the T (P < 0.001), N (P < 0.001), M stages (P = 0.007) and gross ETE (P < 0.001). Together, our results prove that CHI3L1 is a positive regulator of malignant development of PTC, and it promotes proliferation, invasion, and metastasis of PTC cells. Our study improves understanding of the molecular mechanisms underlying the progression of PTC and provides new insights for the clinical diagnosis and treatment of PTC. [ABSTRACT FROM AUTHOR]

As one of the most aggressive malignant tumors, pancreatic ductal adenocarcinoma (PDAC) ranks as the fourth cancer-related mortality in the world. The extremely low survival rate is closely related to early invasion and distant metastasis. However, effective target therapy for weakening its malignant behavior remains limited. Over the past decades, many proteins correlating with invasion and metastasis of PDAC have been discovered using proteomics. The discovery of these proteins gives us a deeper understanding of the invasive and migratory processes of PDAC. This review is a systemic integration of these proteomics findings over the past 10 years. The discovered proteins were typically associated with the glycolytic process, hypoxic microenvironment, post-translational modification, extracellular matrix, exosomes, cancer stem cells, and immune escape. Some proteins were found to have multiple functions, and, cooperation between different proteins in the invasive and metastatic processes was found. This cooperation, and not just single protein function, may play a more significant role in the poor prognosis of PDAC. Therefore, multi-target therapy against these cooperative networks should be a primary choice in the future. [ABSTRACT FROM AUTHOR]

Copyright of Journal of New Medicine is the property of Sun Yat Sen University and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Lung cancer is the most prevalent oncological disease worldwide, with non-small-cell lung cancer accounting for approximately 85% of lung cancer cases. Tripterygium wilfordii is a traditional Chinese herb that is widely used to treat rheumatism, pain, inflammation, tumors, and other diseases. In this study, we found that Triptonodiol extracted from Tripterygium wilfordii inhibited the migration and invasion of non-small-cell lung cancer and inhibited cytoskeletal remodeling, which has not been previously reported. Triptonodiol significantly inhibited the motility activity of NSCLC at low toxic concentrations and suppressed the migration and invasion of NSCLC. These results can be confirmed by wound healing, cell trajectory tracking, and Transwell assays. We found that cytoskeletal remodeling was inhibited in Triptonodiol-treated NSCLC, as evidenced by the reduced aggregation of actin and altered pseudopod morphology. Additionally, this study found that Triptonodiol induced an increase in complete autophagic flux in NSCLC. This study suggests that Triptonodiol reduces the aggressive phenotype of NSCLC by inhibiting cytoskeletal remodeling and is a promising anti-tumor compound. [ABSTRACT FROM AUTHOR]

To study the inhibitory effect of β-elemene on invasion and metastasis of colorectal cancer cells and its possible mechanism. Human colon cancer HCT116 cells were treated with different concentrations of β-elemene. The proliferation inhibition rate of the cells was detected by MTT assay, cell migration rate was detected by scratched assay, and cell invasion rate was evaluated by Transwell cell invasion assay. The expressions of Vimentin, E-cadherin, N-cadherin, and β-catenin were detected by Western blotting. The mRNA expressions of Vimentin, E-cadherin, N-cadherin, and β-catenin were detected by real-time PCR. Compared with the control group, the expressions of migration rate, invasion rate, scratch healing rate, N-cadherin, and Vimentin protein of HCT116 cells were decreased after β-elemene treatment, while the expression of E-cadherin protein was increased, and the inhibition rate of cell proliferation was increased (p<0.05). β-Elemene may inhibit cell proliferation and invasion and metastasis by inhibiting EMT signaling pathway in human colon cancer cell line HCT116. [ABSTRACT FROM AUTHOR]

Necroptosis, pro-inflammatory programmed necrosis, has been reported to exert momentous roles in pancreatic cancer (PC). Herein, the objective of this study is to construct a necroptosis-related prognostic model for detecting pancreatic cancer. In this study, the intersection between necroptosis-related genes and differentially expressed genes (DEGs) of pancreatic ductal adenocarcinoma (PDAC) was obtained based on GeneCards database, GEO database (GSE28735 and GSE15471), and verified using The Cancer Genome Atlas (TCGA). Next, a prognostic model with Cox and LASSO regression analysis, and divided the patients into high-risk and low-risk groups. Subsequently, the Kaplan–Meier (KM) survival curve and the receiver operating characteristic (ROC) curves were generated to assess the predictive ability of overall survival (OS) of PC patients. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to predict the potential biofunction and possible mechanical pathways. The EMTome database and an immune analysis were applied to further explore underlying mechanism. Finally, clinical samples of PDAC patients were utilized to verify the expression of model genes via immunohistochemistry (IHC), and the normal human pancreatic ductal cell line, hTERT-HPNE as well as human pancreatic ductal carcinoma cell lines, PANC-1 and PL45, were used to identify the levels of model genes by Western blot (WB) and immunofluorescence (IF) in vitro. The results showed that 13 necroptosis-related DEGs (NRDEGs) were screened based on GEO database, and finally four of five prognostic genes, including KRT7, KRT19, IGF2BP3, CXCL5, were further identified by TCGA to successfully construct a prognostic model. Univariate and multivariate Cox analysis ultimately confirmed that this prognostic model has independent prognostic significance, KM curve suggested that the OS of low-risk group was longer than high-risk group, and the area under receiver (AUC) of ROC for 1, 3, 5 years was 0.733, 0.749 and 0.667, respectively. A GO analysis illustrated that model genes may participate in cell–cell junction, cadherin binding, cell adhesion molecule binding, and neutrophil migration and chemotaxis, while KEGG showed involvement in PI3K-Akt signaling pathway, ECMreceptor interaction, IL-17 signaling pathway, TNF signaling pathway, etc. Moreover, our results showed KRT7 and KRT19 were closely related to EMT markers, and EMTome database manifested that KRT7 and KRT19 are highly expressed in both primary and metastatic pancreatic cancer, declaring that model genes promoted invasion and metastasis potential through EMT. In addition, four model genes were positively correlated with Th2, which has been reported to take part in promoting immune escape, while model genes except CXCL5 were negatively correlated with TFH cells, indicating that model genes may participate in immunity. Additionally, IHC results showed that model genes were higher expressed in PC tissues than that in adjacent tumor tissues, and WB and IF also suggested that model genes were more highly expressed in PANC-1 and PL45 than in hTERT-HPNE. Tracing of a necroptosis-related prognostic model for pancreatic carcinoma reveals its invasion and metastasis potential through EMT and immunity. The construction of this model and the possible mechanism of necroptosis in PDAC was preliminarily explored to provide reliable new biomarkers for the early diagnosis, treatment, and prognosis for pancreatic cancer patients. [ABSTRACT FROM AUTHOR]