Epithelial-mesenchymal Transition In Cancer Cells Research Articles

Identification of matrix-remodeling associated 5 as a possible molecular oncotarget of pancreatic cancer

Pancreatic cancer has an extremely poor prognosis. Here we examined expression, potential functions and underlying mechanisms of MXRA5 (matrix remodeling associated 5) in pancreatic cancer. Bioinformatics studies revealed that MXRA5 transcripts are significantly elevated in pancreatic cancer tissues, correlating with the poor overall survival, high T-stage, N1 and pathologic stage of the patients. MXRA5 mRNA and protein expression is significantly elevated in microarray pancreatic cancer tissues and different pancreatic cancer cells. In primary and immortalized (BxPC-3 and PANC-1 lines) pancreatic cancer cells, shRNA-induced MXRA5 silencing or CRISPR/Cas9-mediated MXRA5 knockout suppressed cell survival, proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), while provoking cell apoptosis. Conversely, forced overexpression of MXRA5 further promoted pancreatic cancer cell progression and EMT. Bioinformatics studies and the protein chip analyses revealed that differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) in MXRA5-overexpressed primary pancreatic cancer cells were enriched in the PI3K-Akt-mTOR cascade. Indeed, Akt-mTOR activation in primary human pancreatic cancer cells was inhibited by MXRA5 shRNA or knockout, but was augmented following MXRA5 overexpression. In vivo, the growth of MXRA5 KO PANC-1 xenografts was largely inhibited in nude mice. Moreover, intratumoral injection of adeno-associated virus-packed MXRA5 shRNA potently inhibited primary pancreatic cancer cell growth in nude mice. Akt-mTOR activation was also largely inhibited in the MXRA5-depleted pancreatic cancer xenografts. Contrarily MXRA5 overexpression promoted primary pancreatic cancer cell growth in nude mice. Together, overexpressed MXRA5 is important for pancreatic cancer cell growth possibly through promoting EMT and Akt-mTOR activation. MXRA5 could be a potential therapeutic oncotarget for pancreatic cancer.

Extracellular vesicles derived from lung cancer cells promote the progression of lung cancer by delivering miR-151a-5p

Extracellular vesicles (EVs) participate in the occurrence and development of lung cancer. MiR-151a-5p has been reported to be highly expressed in the tumor tissues of lung cancer. The aim of this work was to investigate whether EVs can affect lung cancer progression by delivering miR-151a-5p. In this work, we found that miR-151a-5p was highly expressed in serum of lung cancer patients. Up-regulation of miR-151a-5p and down-regulation of Nedd4-binding partner-1 (N4BP1) were observed in lung cancer cell lines. The expression of miR-151a-5p was also increased in H520-derived EVs. H520-derived EVs promoted cell proliferation, inhibited apoptosis of H520 cells by delivering miR-151a-5p. EVs containing miR-151a-5p repressed E-cadherin expression and elevated N-cadherin and Vimentin expression to impede epithelial-mesenchymal transition (EMT) of H520 cells. Additionally, the interaction between miR-151a-5p and N4BP1 was verified by luciferase reporter assay, showing that miR-151a-5p interacted with N4BP1. MiR-151a-5p repressed N4BP1 expression by interacting with N4BP1. EVs containing miR-151a-5p promoted malignant phenotypes of H520 cells by targeting N4BP1. Finally, a tumor-bearing mouse model was constructed by inoculation of H520 cells with miR-151a-5p overexpression or knockdown. Overexpression of miR-151a-5p accelerated tumor growth of lung cancer in vivo, and repressed N4BP1 expression in the tumor tissues. Knockdown of miR-151a-5p caused opposite results. In conclusion, this work demonstrated that lung cancer cell-derived EVs secreted miR-151a-5p to promote cell proliferation, and inhibit apoptosis and EMT of lung cancer cells by targeting N4BP1, thereby accelerating lung cancer progression. Thus, this study suggests that EVs-derived miR-151a-5p may be a potential target for lung cancer treatment.

Juglone Inhibits Tumor Metastasis by Regulating Stemness Characteristics and the Epithelial-to-Mesenchymal Transition in Cancer Cells both in Vitro and in Vivo.

The stemness characteristics of cancer cells, such as self-renewal and tumorigenicity, are considered to be responsible, in part, for tumor metastasis. Epithelial-to-mesenchymal transition (EMT) plays an important role in promoting both stemness and tumor metastasis. Although the traditional medicine juglone is thought to play an anticancer role by affecting cell cycle arrest, induction of apoptosis, and immune regulation, a potential function of juglone in regulating cancer cell stemness characteristics remains unknown. In the present study, tumor sphere formation assay and limiting dilution cell transplantation assays were performed to assess the function of juglone in regulating maintenance of cancer cell stemness characteristics. EMT of cancer cells was assessed by western blot and transwell assay in vitro, and a liver metastasis model was also performed to demonstrate the effect of juglone on colorectal cancer cells in vivo. Data gathered indicates juglone inhibits stemness characteristics and EMT in cancer cells. Furthermore, we verified that metastasis was suppressed by juglone treatment. We also observed that these effects were, in part, achieved by inhibiting Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1). These results indicate that juglone inhibits maintenance of stemness characteristics and metastasis in cancer cells.

Hsa-miR-22-3p inhibits liver cancer cell EMT and cell migration/ invasion by indirectly regulating SPRY2.

The general mechanism for microRNAs to play biological function is through their inhibition on the expression of their target genes. In cancer, microRNAs may accelerate cell senescence, block angiogenesis, decrease energy supplies, repress tumor cell cycle and promote apoptosis to function as the tumor repressors. On the other hand, microRNAs can modulate tumor suppressor molecules to activate oncogene relevant signaling pathway to initiate tumorigenesis and promote tumor progression. By targeting different genes, miR-22 can function as either a tumor suppressor or a tumor promoter in different types of cancer. In liver cancer, miR-22 mainly functions as a tumor suppressor via its regulation on different genes. In this study, we demonstrated that miR-22 indirectly regulates SPRY2 by inhibiting CBL, an E3 ligase for SPRY2 that has been confirmed. As one of the modulators of the MAPK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinase) signaling pathway, SPRY2 plays important roles in many developmental and physiological processes, and its deregulation has been reported in different types of cancer and shown to affect cancer development, progression, and metastasis. By inhibiting the expression of CBL, which stabilizes SPRY2, miR-22 indirectly upregulates SPRY2, thereby suppressing the epithelial-mesenchymal transition (EMT), cell migration, and invasion and decreasing the expression of liver cancer stem cell (CSC) marker genes. The inhibitory effects of miR-22 on EMT, cell migration, and invasion can be blocked by the knockdown of SPRY2 expression in miR-22 overexpressing cells. Additionally, we demonstrated that miR-22 expression inhibits the ERK signaling pathway and that this effect is due to its upregulation of SPRY2. Overall, our study revealed a novel miR-22-3p/CBL/SPRY2/ERK axis that plays an important role in EMT, cell migration, and invasion of liver cancer cells.

Sildenafil Inhibits the Growth and Epithelial-to-mesenchymal Transition of Cervical Cancer via the TGF-β1/Smad2/3 Pathway.

The study aims to explore new potential treatments for cervical cancer. Cervical cancer is the second most common cancer in women, causing >250,000 deaths worldwide. Patients with cervical cancer are mainly treated with platinum compounds, which often cause severe toxic reactions. Furthermore, the long-term use of platinum compounds can reduce the sensitivity of cancer cells to chemotherapy and increase the drug resistance of cervical cancer. Therefore, exploring new treatment options is meaningful for cervical cancer. The present study was to investigate the effect of sildenafil on the growth and epithelial-tomesenchymal transition (EMT) of cervical cancer. HeLa and SiHa cells were treated with sildenafil for different durations. Cell viability, clonogenicity, wound healing, and Transwell assays were performed. The levels of transforming growth factor-β1 (TGF-β1), transforming growth factor-β type I receptor (TβRI), phosphorylated (p-) Smad2 and p-Smad3 in cervical cancer samples were measured. TGF-β1, Smad2 or Smad3 were overexpressed in HeLa cells, and we measured the expression of EMT marker proteins and the changes in cell viability, colony formation, etc. Finally, HeLa cells were used to establish a nude mouse xenograft model with sildenafil treatment. The survival rate of mice and the tumor size were recorded. High concentrations of sildenafil (1.0-2.0 μM) reduced cell viability, the number of HeLa and SiHa colonies, and the invasion/migration ability of HeLa and SiHa cells in a dose- and time-dependent manner. The expression of TGF-β1, TβRI, p-Smad2 and p-Smad3 was significantly enhanced in cervical cancer samples and cervical cancer cell lines. Sildenafil inhibited the expression of TGF-β1-induced EMT marker proteins (Snail, vimentin, Twist, E-cadherin and N-cadherin) and p-Smad2/3 in HeLa cells. Overexpression of TGF-β1, Smad2, and Smad3 reversed the effect of sildenafil on EMT, viability, colony formation, migration, and invasion ability of HeLa cells. In the in vivo study, sildenafil significantly increased mouse survival rates and suppressed xenograft growth. Sildenafil inhibits the proliferation, invasion ability, and EMT of human cervical cancer cells by regulating the TGF-β1/Smad2/3 pathway.

Identification of key molecules in miRNA-mRNA regulatory network associated with high-grade serous ovarian cancer recurrence using bioinformatic analysis

To investigate the correlation of the potential functional microRNA (miRNA)-mRNA regulatory network with recurrence of high-grade serous ovarian carcinoma (HGSOC) and its biological significance. This study was performed based on the data of 354 patients with HGSOC from the Cancer Genome Atlas database. In these patients, HGSOC was divided into different subtypes based on the pathways identified by GO analysis, and the correlations of the subtypes with HGSOC recurrence and differentially expressed miRNAs and mRNAs were assessed. Two relapse-related datasets were identified using the Gene Set Enrichment (GSE) database, from which the differentially expressed miRNAs were identified by intersection with the TCGA data. The target genes of these miRNAs were predicted using miRWalk 2.0 database, and these common differentially expressed miRNAs and mRNAs were used to construct the key miRNA-mRNA network associated with HGSOC recurrence. The expression of miR-506-3p and SNAI2 in two ovarian cancer cell lines was detected using RT-qPCR and Western blotting, and their targeted binding was verified using a double luciferase assay. The effect of miR-506-3p expression modulation on ovarian cancer cell migration was detected using scratch assay and Transwell assay. We screened 303 GO terms of HGSOC-related pathways and identified two HGSOC subtypes (C1 and C2). The subtype C1 was associated with a significantly higher recurrence rate than C2. The differentially expressed genes between C1 and C2 subtypes were mainly enriched in epithelial-mesenchymal transition (EMT). Five miRNAs were identified as potential regulators of EMT, and a total of 41 target genes were found to be involved in the differential expressions of EMT pathway between C1 and C2 subtypes. The key miRNA-mRNA network associated with HGSOC recurrence was constructed based on these 5 miRNAs and 41 mRNAs. MiR-506-3p was confirmed to bind to SNAI2, and up-regulation of miR-506-3p significantly inhibited SNAI2 expression and reduced migration and invasion of SKOV3 and CAOV3 cells (P < 0.05), while miR-506-3p knockdown produced the opposite effects (P < 0.05). MiR-506-3p and SNAI2 are the key molecules associated with HGSOC recurrence. MiR-506-3p may affect EMT of ovarian cancer cells by regulating cell migration and invasion via SNAI2, and its expression level has predictive value for HGSOC recurrence.

Combination Treatment of a Phytochemical and a Histone Demethylase Inhibitor-A Novel Approach towards Targeting TGFβ-Induced EMT, Invasion, and Migration in Prostate Cancer.

Minimizing side effects, overcoming cancer drug resistance, and preventing metastasis of cancer cells are of growing interest in current cancer therapeutics. Phytochemicals are being researched in depth as they are protective to normal cells and have fewer side effects. Hesperetin is a citrus bioflavonoid known to inhibit TGFβ-induced epithelial-to-mesenchymal transition (EMT), migration, and invasion of prostate cancer cells. Targeting epigenetic modifications that cause cancer is another class of upcoming therapeutics, as these changes are reversible. Global H3K27me3 levels have been found to be reduced in invasive prostate adenocarcinomas. Combining a demethylase inhibitor and a known anti-cancer phytochemical is a unique approach to targeting cancer to attain the aforementioned objectives. In the current study, we used an H3K27 demethylase (JMJD3/KDM6B) inhibitor to study its effects on TGFβ-induced EMT in prostate cancer cells. We then gave a combined hesperetin and GSK-J4 treatment to the PC-3 and LNCaP cells. There was a dose-dependent increase in cytotoxicity and inhibition of TGFβ-induced migration and invasion of prostate cancer cells after GSK-J4 treatment. GSK-J4 not only induced trimethylation of H3K27 but also induced the trimethylation of H3K4. Surprisingly, there was a reduction in the H3K9me3 levels. GSK-J4 alone and a combination of hesperetin and GSK-J4 treatment effectively inhibit the important hallmarks of cancer, such as cell proliferation, migration, and invasion, by altering the epigenetic landscape of cancer cells.

Heat treatment-induced autophagy promotes breast cancer cell invasion and metastasis via TGF-β2-mediated epithelial-mesenchymal transitions.

Insufficient thermal ablation can accelerate malignant behaviors and metastases in some solid tumors, and epithelial-mesenchymal transition (EMT) and autophagy are involved in tumor metastasis. It has been found that TGF-β2 which belongs to the family of transforming growth factors often associated with cancer cell invasiveness and EMT. However, whether the interactions between autophagy and TGF-β2 induce EMT in breast cancer (BC) cells following insufficient microwave ablation (MWA) remains unclear. BC cells were treated with sublethal heat treatment to simulate insufficient MWA, and the effects of heat treatment on the BC cell phenotypes were explored. CCK-8, colony formation, flow cytometry, Transwell, and wound healing assays were performed to evaluate the influence of sublethal heat treatment on the proliferation, apoptosis, invasion, and migration of BC cells. Western blotting, real-time quantitative PCR, immunofluorescence, and transmission electron microscopy were carried out to determine the changes in markers associated with autophagy and EMT following sublethal heat treatment. Results showed that heat treatment promoted the proliferation of surviving BC cells, which was accompanied by autophagy induction. Heat treatment-induced autophagy up-regulated TGF-β2/Smad2 signaling and promoted EMT phenotype, thereby enhancing BC cells' migration and invasion abilities. An increase or decrease of TGF-β2 expression resulted in the potentiation and suppression of autophagy, as well as the enhancement and abatement of EMT. Autophagy inhibitors facilitated apoptosis and repressed proliferation of BC cells in vitro, and thwarted BC cell tumor growth and pulmonary metastasis in vivo. Heat treatment-induced autophagy promoted invasion and metastasis via TGF-β2/Smad2-mediated EMTs. Suppressing autophagy may be a suitable strategy for overcoming the progression and metastasis of residual BC cells following insufficient MWA.

ISLR interacts with MGAT5 to promote the malignant progression of human gastric cancer AGS cells.

Gastric cancer is a common malignant tumor with high morbidity and mortality. The present study aimed to investigate the role of the immunoglobulin superfamily containing leucine-rich repeat (ISLR) gene in gastric cancer and examine whether ISLR could interact with N-acetylglucosaminyltransferase V (MGAT5) to affect the malignant progression of gastric cancer. The expression of ISLR and MGAT5 in human normal gastric epithelial cells and human gastric cancer cells, and the transfection efficiency of ISLR interference plasmids and MGAT5 overexpression plasmids were all detected by reverse transcription-quantitative PCR (RT-qPCR) and western blot. The viability, proliferation, migration and invasion, and epithelial-mesenchymal transition (EMT) of gastric cancer cells after indicated transfection were detected by Cell counting kit-8 (CCK-8) assay, 5-ethynyl-2'-deoxyuridine (EdU) staining, wound healing assay, and transwell assay. The interaction between ISLR and MGAT5 was confirmed by co-immunoprecipitation. The expression of proteins related to migration, invasion, and EMT was detected by immunofluorescence and western blot. As a result, ISLR was highly expressed in gastric cancer and was associated with poor prognosis. Interference with ISLR inhibited the viability, proliferation, migration, invasion, and EMT of gastric cancer cells. ISLR interacted with MGAT5 in gastric cancer cells. MGAT5 overexpression weakened the effects of ISLR knockdown on suppressing the viability, proliferation, migration, invasion, and EMT of gastric cancer cells. ISLR interacted with MGAT5 to promote the malignant progression of gastric cancer.

LSD1 silencing inhibits the proliferation, migration, invasion, and epithelial-to-mesenchymal transition of hypopharyngeal cancer cells by inducing autophagy and pyroptosis.

Hypopharyngeal cancer is a subtype of the head and neck malignancies. We aimed to explore the role of lysine-specific demethylase 1 (LSD1/KDM1A) in the progression of hypopharyngeal cancer and to identify the potential mechanisms. First, LSD1 expression in head and neck squamous cell carcinoma (HNSCC) tissues and the correlation between LSD1 and the stage of HNSC were analyzed by the University of ALabama at Birmingham CANcer data analysis Portal (UALCAN). Following LSD1 silencing, proliferation of pharyngeal cancer cell line FaDu cells was evaluated by cell counting kit-8 and colony formation assays. Wounding healing and transwell assays were used to measure the capacities of migration and invasion. In addition, expression of proteins related to epithelial-to-mesenchymal transition (EMT), autophagy, and pyroptosis was tested by Western blot analysis or immunofluorescence. After treatment with autophagy inhibitor 3-methyladenine (3-MA) or NLR family pyrin domain containing 3 (NLRP3) inhibitor MCC950, the malignant biological properties were measured again. High LSD1 expression was observed in HNSC tissues, which was correlated with stage. LSD1 knockdown significantly suppressed the proliferation, migration, invasion, and EMT of hypopharyngeal cancer cells. Moreover, autophagy and pyroptosis were induced by LSD1 depletion, observed by the enhanced fluorescence intensity of LC3, gasdermin-D (GSDMD)-N, and apoptosis-associated speck-like protein containing a CARD (ASC), accompanied by upregulated expression of LC3II/LC3I, Beclin-1, NLRP3, cleaved-caspase 1, ASC, interleukin (IL)-1β, and IL-18 and downregulated expression of p62. Importantly, 3-MA or MCC950 addition obviously reversed the inhibitory effects of LSD1 silencing on the proliferation, migration, invasion, and EMT of hypopharyngeal cancer cells. To sum up, LSD1 silencing could restrain the progression of hypopharyngeal cancer cells by inducing autophagy and pyroptosis.

MLL3 loss drives metastasis by promoting a hybrid epithelial-mesenchymal transition state.

Phenotypic plasticity associated with the hybrid epithelial-mesenchymal transition (EMT) is crucial to metastatic seeding and outgrowth. However, the mechanisms governing the hybrid EMT state remain poorly defined. Here we showed that deletion of the epigenetic regulator MLL3, a tumour suppressor frequently altered in human cancer, promoted the acquisition of hybrid EMT in breast cancer cells. Distinct from other EMT regulators that mediate only unidirectional changes, MLL3 loss enhanced responses to stimuli inducing EMT and mesenchymal-epithelial transition in epithelial and mesenchymal cells, respectively. Consequently, MLL3 loss greatly increased metastasis by enhancing metastatic colonization. Mechanistically, MLL3 loss led to increased IFNγ signalling, which contributed to the induction of hybrid EMT cells and enhanced metastatic capacity. Furthermore, BET inhibition effectively suppressed the growth of MLL3-mutant primary tumours and metastases. These results uncovered MLL3 mutation as a key driver of hybrid EMT and metastasis in breast cancer that could be targeted therapeutically.

Anti-oncogenic mechanism of KLF17 in colon cancer by repressing cell migration and invasion via FHL1 upregulation.

Colon cancer is a disease with high prevalence worldwide. This study sought to investigate Kruppel-like factor 17 (KLF17) mechanism in the development of colon cancer through four-and-a-half-LIM domain protein 1 (FHL1). In colon cancer cells, KLF17 and FHL1 expression was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot. After gain- and loss-of-function experiments in colon cancer cells, cell proliferative, invasive, and migrating abilities were tested by cell counting kit-8, transwell, and scratch assays, respectively. The expression of epithelial-mesenchymal transition (EMT)-related genes, E-cadherin, N-cadherin, and Vimentin, was measured by RT-qPCR and Western blot. Chromatin immunoprecipitation and dual-luciferase reporter gene assays were performed to detect the binding of KLF17 and the FHL1 promoter. Finally, a transplantation tumor model in nude mice was established for in vivo validation. Mechanistically, KLF17 facilitated FHL1 transcription by binding to the FHL1 promoter. KLF17 or FHL1 upregulation suppressed the colon cancer cell proliferative, invasive, and migrating capacities, accompanied by elevated E-cadherin expression and diminished N-cadherin and Vimentin expression. Furthermore, FHL1 silencing abrogated the repressive impacts of KLF17 upregulation on colon cancer cell EMT, proliferative, invasive, and migrating capabilities. Furthermore, KLF17 augmented FHL1 expression and curtailed the growth of transplanted tumors in nude mice. Conclusively, KLF17 promoted FHL1 transcription, thereby impeding the invasion, migration, and EMT of colon cancer cells.

Somatostatin Inhibited the EMT of Pancreatic Cancer Cells by Mediating the TGF-β/Smad Signaling Pathway.

Pancreatic cancer (PC), a commonly recognized malignancy, arises within the digestive tract. Somatostatin (SOM) is a regulatory peptide that acts on secretion in vivo. Several studies have shown that SOM has inhibitory effects on various cancers. This work aims to probe the inhibitory effect, and mechanism of SOM action, on the epithelial-mesenchymal transition (EMT) of PC cells. First, the effects of SOM and transforming growth factor-β (TGF-β) on the proliferation of PC cells was determined by Cell Counting Kit-8 (CCK-8) assay. Next, we assessed the impact of SOM and TGF-β on the metastasis and apoptosis of PC cells using transwell assays and flow cytometry. Finally, we evaluated the effects of SOM and TGF-β on the expression of EMT-related proteins, apoptosis-related proteins, and proteins related to the TGF-β/Smad signaling pathway in PC cells using western blot analysis. SOM suppressed the growth and metastasis of PC cells, and facilitated their apoptosis (p < 0.05). Moreover, SOM reversed pro-apoptotic effects of TGF-β (p < 0.05). Specifically, SOM increased the expression of Cysteine-aspartic acid protease 3 (Caspase-3) and Bcl-2-associated X protein (Bax) proteins while reducing the expression of B-cell lymphoma 2 (Bcl-2) protein (p < 0.05). SOM also reversed the TGF-β-induced EMT process. The TGF-β1, Smad2, and Smad3 proteins in PC cells treated with SOM were significantly down-regulated (p < 0.05). SOM suppressed the EMT progression in PC cells through its regulation of the TGF-β/Smad signaling pathway.

CXCL14 promotes metastasis of non-small cell lung cancer through ACKR2-depended signaling pathway.

Background: Lung cancer is a malignant tumor with metastatic potential. Chemokine ligand 14 (CXCL14) has been reported to be associated with different cancer cell migration and invasion. However, few studies have explored the function of CXCL14 and its specific receptor in lung cancer metastasis. This study aims to determine the mechanism of CXCL14-promoted cancer metastasis. Methods: The expression of CXCL14, atypical chemokine receptor 2 (ACKR2), and epithelial mesenchymal transition (EMT) markers was evaluated by the public database of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), Western blot, enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qPCR), immunohistochemistry (IHC), and immunofluorescence (IF). Migration and wound healing assays were used to observe the motility of cancer cells. A luciferase reporter assay was performed to analyze transcription factor activity. The metastasis of lung cancer cells was evaluated in an orthotopic model. Results: We have presented that overexpression of CXCL14 and ACKR2 was observed in lung cancer datasets, human lung tumor sections, and lung cancer cells. Furthermore, the migration of CXCL14-promoted lung cancer cells was determined in vitro and in vivo. In particular, ACKR2 knockdown abolished CXCL14-induced cancer cell motility. Additionally, ACKR2 was involved in CXCL14-triggered phospholipase Cβ3 (PLCβ3), protein kinase Cα (PKCα), and proto-oncogene c-Src signaling pathway and subsequently upregulated nuclear factor κB (NF-κB) transcription activity leading to EMT and migration of lung cancer cells. These results indicated that the CXCL14/ACKR2 axis played an important role in lung cancer metastasis. Conclusion: This study is the first to reveal the function of CXCL14 in promoting EMT and metastasis in lung cancer. As a specific receptor for CXCL14 in lung cancer, ACKR2 mediates CXCL14-induced signaling that leads to cell motility. Our findings can be used as a prognostic biomarker of lung cancer metastasis.

BML-111, the agonist of lipoxin A4, suppresses epithelial-mesenchymal transition and migration of MCF-7 cells via regulating the lipoxygenase pathway.

Introduction: Aberrant epithelial-mesenchymal transition (EMT) and migration frequently occur during tumour progression. BML-111, an analogue of lipoxin A4, has been implicated in inflammation in cancer research. Methods: 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, western blot, Reverse Transcription Polymerase Chain Reaction (RT-PCR), transwell assay, immunofluorescence, and immunohistochemistry were conducted in this study. Results: In vitro experiments revealed that BML-111 inhibited EMT and migration in CoCl2-stimulated MCF-7 cells. These effects were achieved by inhibiting MMP-2 and MMP-9, which are downregulated by 5-lipoxygenase (5-LOX). Moreover, BML-111 inhibited EMT and migration of breast cancer cells in BALB/c nude mice inoculated with MCF-7 cells. Conclusion: Our results suggest that BML-111 may be a potential therapeutic drug for breast cancer and that blocking the 5-LOX pathway could be a possible approach for mining effective drug targets.

Zinc Finger Protein 479 Promotes Metastasis and Epithelial-Mesenchymal Transition in Gastric Cancer via MEK/ERK/DNMT1 Signaling Pathway

The carcinogenic function of zinc finger protein 479 (ZNF479) has been found in a few sorts of cancer. However, the part of ZNF479 in gastric cancer remains vague. In this study, the effect of ZNF479 on gastric cancer cell survival, metastasis and epithelial mesenchymal transition (EMT) was investigated using the Cell Counting Kit-8 (CCK-8), flow cytometry, and transwell assays. Immunofluorescence assay and Western blot was carried out to evaluate the levels of cell cycle, EMT, and MEK/ERK/DNMT1 pathway-related proteins. A lung metastasis cancer mice model was constructed to evaluate the function of ZNF479 on tumor metastasis in vivo. We noticed that overexpression of ZNF479 promoted cell growth, cell cycle progression, invasion and EMT of gastric cancer cells, whereas ZNF479 knockdown appeared the inverse comes about. Moreover, downregulation of ZNF479 hindered tumor metastasis in mice. Advanced investigation implied that ZNF479 was engaged in the regulation of gastric cancer progression by affecting the MEK/ERK/DNMT1 pathway for that the MEK-specific inhibitor PD98059 reversed the impact of ZNF479 overexpression on gastric cancer cells and repressed MEK/ERK/DNMT1 signal. In conclusion, ZNF479 promotes gastric cancer cells by activating the MEK/ERK/DNMT1 pathway, ZNF479 may give a new and viable gene target for gastric cancer intercession.

MICRORNA-31 AS A POTENTIAL THERAPEUTIC BIOMARKER FORORAL SQUAMOUS CELL CARCINOMA: CURRENT EVIDENCE AND FUTURE PROSPECTS.

Dear Editor,&#x0D; Cancer is a foremost death cause in each country and a substantial hindrance to improving life expectancy, accounting for more than 10 million fatalities in 2020, or around one in every six fatalities [1]. Oral cancer is among the leading causes of cancer-related mortality in developing countries. Oral squamous cell carcinoma (OSCC) is a widespread type of malignancy associated with tobacco usage and human papilloma virus infection. The majority of people are diagnosed with cancer at an advanced stage, the 5-year survival rate for OSCC patients is only around 50%. Despite biological and technological advances, in recent decades, the prognosis for OSCC has not improved, and its occurrence has increased. Identification of biomarkers that can be utilized to establish an early diagnosis or predict tumor growth is enabled by determining which molecular pathways are disrupted [2].&#x0D; MicroRNAs, which can serve as both oncogenes and tumor-inhibiting factors, are misaligned in a wide range of cancers [3]. These are short, noncoding RNAs that affect protein expression following transcription at the post-transcriptional level. MicroRNAs play a vital role in proliferation, differentiation, apoptosis, immune response, and angiogenesis, among other things in the pathogenesis of cancer. Multiple researchers have documented that specific microRNAs are frequently down regulated in cancers, implying that they operate as tumor suppressors by targeting many oncogenes. According to research conducted by O’Brien et al, altering levels of microRNAs expression can improve chemotherapeutic efficacy [4]. In recent decades, several researches have linked metastasis, survival, and recurrence of OSCC patients to miRNA expression [5].&#x0D; MicroRNA-31, a gene on chromosome 9p21.3, was one of the first mammalian microRNAs discovered. Several studies have been conducted to evaluate the functions of miR-31 in carcinogenesis and the progression of OSCC. A prior clinical investigation conducted by Liu et al. [6] revealed that miR-31 levels in plasma were considerably increased in patients with OSCC when compared to age and gender-matched control participants. Several studies show that miR-31 performs a role in cancer etiology and aggressiveness via altering target genes. According to reports, miR-31 regulates a number of genes, including fibronectin type III domain containing 5, special AT-rich sequence-binding protein-2, large tumor suppressor kinase 2 (LATS2), tensin 1, AT-rich interaction domain 1A, and hypoxia-inducible factor-1 [7]. The concentration of miR-31 expression in serum, urine, saliva and organ tissue can be utilized as a diagnostic and predictive biomarker for a variety of malignancies [8].&#x0D; A recent investigation by Chou et al. [9] found that miR-31 levels were significantly raised in OSCC cells and tumor tissues, and that the miR-31 gene locus was necessary to initiate oncogenesis in OSCC. Upregulation of miR-31 contributes to the formation of OSCC by interacting with certain genes and signaling pathways that impact cancer cell cycle, epithelial-mesenchymal transition and cell proliferation. miR-31 forms a complex network with direct target genes (such as RHOA, FIH, ACOX1, VEGF, SIRT3, LATS2, KANK1, and NUMB) and initiates several signaling pathways including the ERK-MMP9 cascade, the Hippo pathway, Wnt signaling, and the MCT1/MCT4 regulatory cascade [10]. MiR-31 interacts with a number of proteins and pathways that are crucial in OSCC and it is overexpressed in plasma, saliva, and OSCC tumor tissue. However, more research is needed to fully comprehend the molecular mechanisms by which miR-31 drives OSCC malignancy, paving the way for the development of miR-31 based diagnostic, prognostic, and predictive biomarkers for OSCC.

Epithelial-Mesenchymal Transition Induced in Cancer Cells by Adhesion to Type I Collagen.

The epithelial-mesenchymal transition (EMT) is an important biological process that is physiologically observed during development, wound healing, and cancer invasion. During EMT induction, cancer cells lose their epithelial properties owing to various tumor microenvironmental factors and begin to exhibit mesenchymal properties, such as loss of apical-basal polarity, weakened intercellular adhesion, and promotion of single cell migration. Several factors, including growth factor stimulation and adhesion to type I collagen (Col-I), induce EMT in cancer cells. Cells adhere to Col-I via specific receptors and induce EMT by activating outside-in signals. In vivo, Col-I molecules often form fibrils, which then assemble into supramolecular structures (gel form). Col-I also self-assembles in vitro under physiological conditions. Notably, Col-I can be used as a culture substrate in both gel and non-gel forms, and the gel formation state of Col-I affects cell fate. Although EMT can be induced in both forms of Col-I, the effects of gel formation on EMT induction remain unclear and somewhat inconsistent. Therefore, this study reviews the relationship between Col-I gel-forming states and EMT induction in cancer cells.

TAGLN2 Promotes the Proliferation, Migration, Invasion, and EMT of Clear Cell Renal Cell Carcinoma Through the PI3K/Akt Signaling Pathway.

The effect of Transgelin 2 (TAGLN2) on clear cell renal cell carcinoma (ccRCC) is unknown. Thisstudy explored the potential role and mechanism of ccRCC. The expression of TAGLN2 in Pan-cancers was analyzed using the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases. TCGA-KIRC database was used to analyze subsequent prognostic survival, pathway enrichment, and immune infiltration. Relevant experimental methods could explain the effect of TAGLN2 expression on tumor cell proliferation, migration, invasion, and apoptosis. Apoptosis, proliferation, Epithelial-to-Mesenchymal Transition (EMT), and PI3K/AKT signaling pathway-related protein expression were determined through western blotting. In the TCGA + GTEx database, mRNA-TAGLN2 expression was clearly increased in pan-cancer tissues, and the same result was found in ccRCC patients based on KIRC analysis results. In addition, TAGLN2 was associated with poor clinical stage, pathological grade, and survival prognosis. TAGLN2 is highly expressed in ccRCC tissues and in vitro TAGLN2 silencing of cells inhibits the proliferation, migration, invasion, and EMT of ccRCC cancer cells. Furthermore, TAGLN2-related differential genes enriched in the PI3K/AKT signaling pathway were negatively regulated after TAGLN2 silencing. Moreover, TAGLN2 may promote tumor immune escape and increase the risk of distant metastasis in immune infiltration-related analyses. TAGLN2 can be used as a single indicator to explain the survival probability of patients with ccRCC. In vitro TAGLN2 silencing inhibited the malignant properties of ccRCC by blocking the PI3K/AKT signaling pathway. In addition, TAGLN2 contributes to tumor immune escape and may be a potential therapeutic target for ccRCC.

Circ_0018909 knockdown inhibits the development of pancreatic cancer via the miR-545-3p/FASN axis and reduces macrophage polarization to M2.

Multiple circular RNAs (circRNAs) were proven to regulate the development of pancreatic cancer. However, the action of circ_0018909 in pancreatic cancer was still unclear. The expression of circ_0018909, microRNA-545-3p (miR-545-3p), and fatty acid synthase (FASN) was measured using quantitative reverse-transcriptase PCR (qRT-PCR). Cell growth, cell cycle arrest, apoptotic cells, metastasis, and epithelial to mesenchymal transition (EMT) were determined using EdU assay, flow cytometry, wound-healing assay, transwell invasion, and western blotting, respectively. The expression of the macrophage markers, including CD80, MCP-1, iNOS, and IL-6 (M1 markers), as well as CD206 and CD163 (M2 markers), was analyzed using qRT-PCR. Circ_0018909 knockdown dramatically depressed cell growth, migration, invasion, EMT, and elevated the number of apoptotic cells in pancreatic cancer cells, and repressed tumor growth in mice. Moreover, we proved that the absence of miR-545-3p rescued the action of circ_0018909 downregulation on cell growth, metastasis, apoptosis, and EMT in pancreatic cancer cells. MiR-545-3p bound to FASNand FASN overexpression hindered the impacts of miR-545-3p on the progression of pancreatic cancer. Besides this, our data demonstrated that circ_0018909 induced polarization from M0 macrophages to M2 macrophages. Circ_0018909 knockdown retarded the development of pancreatic cancer by modulating miR-545-3p to regulate FASN expression.