Tumor Cell Epithelial-mesenchymal Transition Research Articles

TFEB and TFE3 Depletion Increases Cancer Stem Cell Characteristics and EMT in Triple‐Negative Breast Cancer

Breast cancer is currently the second leading cause of death for women worldwide. One subtype of breast cancer with poor prognosis is triple‐negative breast cancer (TNBC), which is characterized by the lack of expression of estrogen, progesterone, and human epidermal growth factor 2 (HER2) receptors. TNBC is difficult to treat due to its drug resistance and aggressiveness. Tumor invasiveness is driven by epithelial‐mesenchymal transition (EMT), which allows cells to acquire mobility to metastasize. EMT is also relevant to maintaining cancer stem cell (CSC) characteristics. Drug resistance is driven by CSCs, which are slow to divide, thus surviving chemotherapies, the standard of treatment. Thus, new treatments that inhibit CSCs and/or EMT in TNBC are highly desirable. TFEB and TFE3, two transcription factors of the MiT‐TFE family that operate as a complex, are involved in regulating lysosome biogenesis and autophagy. Our preliminary data and other studies have shown that TFEB and TFE3 regulate pluripotency and EMT in various in vitro models such as gastric and pancreatic cancer, but this regulation is poorly understood in TNBC. To develop new targeted therapies for TNBC, this study aimed to investigate the effects of depleting TFEB and TFE3 on CSC abundance and EMT. CSC renewal capacity was assessed via mammosphere assays and flow cytometry using CD44 and ALDH1A. The MDA MB 231 TFEBKO cells grew the highest number and largest mammospheres compared to the control, TFE3 knock‐down, and double knock‐out cell lines. TFEBKO and TFEBKOTFE3sh showed increases in CD44 expression and ALDH1A activity. While ALDH1A positivity was 1.16% in controls, TFEBKO and TFEBKOTFE3sh significantly increased the population to 22.6% and 21.9%, respectively. Western blotting and a wound healing assay were used to evaluate EMT marker expression and migration, respectively. Quantification revealed that TFEBKO had a two‐fold increase in protein expression levels of EMT markers Vimentin, Snail, and Slug, while TFE3sh showed higher protein expression levels of Vimentin and Slug. TFEBKOTFE3sh showed higher protein expression levels of Slug. The TFEBKO cell line had the highest rate of migration when compared to the control. In conclusion, the data showed that knockout of TFEB and combined knockout of TFEB and TFE3 resulted in an increase in stem cell character and EMT, which could correlate to increased tumor metastasis and poorer prognosis. These results are promising to investigate how depletion or inhibition of TFEB and TFE3 can affect TNBC tumor cell stem cell character and EMT.

MiR-16 Inhibits Extracellular Signal-Regulated Kinases (ERK) Mitogen-Activated Protein Kinases (MAPK) Signaling to Affect Epithelial-Mesenchymal Transition (EMT) and Invasion of Glioma Cells

Abnormal MEK1 expression is associated with tumor cell EMT, invasion and metastasis. Decreased miR-16 level is associated with glioma. Bioinformatics analysis showed a relationship between miR-16 and MEK1. This study assessed whether miR-16 regulates MEK1 expression and affects glioma cell EMT and invasion. The tumor tissues and adjacent glioma tissues were collected to measure miR-16 and MEK1 mRNA. The dual luciferase assay validated the relation of miR-16 with MEK1. U251 cells were cultured and assigned into NC group and mimic group, followed by analysis of cell biological behaviors, and MEK1, p-ERK1/2, E-cadherin, N-Cadherin expression. Compared with adjacent tissues, miR-16 expression was significantly decreased and MEK1 was elevated in glioma tissues. Compared with HEB, miR-16 in glioma U251 and SHG44 cells was decreased and MEK1 was increased. Dual luciferase reporter gene experiments confirmed the relation of miR-16 with MEK1. Transfection of miR-16 mimic significantly down-regulated MEK1, p-ERK1/2 and N-cadherin in U251 cells, upregulated E-cadherin, inhibited cell proliferation, promoted apoptosis, and attenuated EMT and invasion of glioma cells. In conclusion, decreased miR-16 expression and increased MEK1 expression is related to glioma pathogenesis. Overexpression of miR-16 can inhibit MEK1 expression, ERK/MAPK signaling, glioma cell proliferation, promote apoptosis, and attenuate EMT and invasion.

Tumor Cell Glycolysis-At the Crossroad of Epithelial-Mesenchymal Transition and Autophagy.

Upregulation of glycolysis, induction of epithelial–mesenchymal transition (EMT) and macroautophagy (hereafter autophagy), are phenotypic changes that occur in tumor cells, in response to similar stimuli, either tumor cell-autonomous or from the tumor microenvironment. Available evidence, herein reviewed, suggests that glycolysis can play a causative role in the induction of EMT and autophagy in tumor cells. Thus, glycolysis has been shown to induce EMT and either induce or inhibit autophagy. Glycolysis-induced autophagy occurs both in the presence (glucose starvation) or absence (glucose sufficiency) of metabolic stress. In order to explain these, in part, contradictory experimental observations, we propose that in the presence of stimuli, tumor cells respond by upregulating glycolysis, which will then induce EMT and inhibit autophagy. In the presence of stimuli and glucose starvation, upregulated glycolysis leads to adenosine monophosphate-activated protein kinase (AMPK) activation and autophagy induction. In the presence of stimuli and glucose sufficiency, upregulated glycolytic enzymes (e.g., aldolase or glyceraldehyde 3-phosphate dehydrogenase) or decreased levels of glycolytic metabolites (e.g., dihydroxyacetone phosphate) may mimic a situation of metabolic stress (herein referred to as “pseudostarvation”), leading, directly or indirectly, to AMPK activation and autophagy induction. We also discuss possible mechanisms, whereby glycolysis can induce a mixed mesenchymal/autophagic phenotype in tumor cells. Subsequently, we address unresolved problems in this field and possible therapeutic consequences.

Targeting type I collagen for cancer treatment

Collagen is the most abundant protein in animals. Interactions between tumor cells and collagen influence every step of tumor development. Type I collagen is the main fibrillar collagen in the extracellular matrix and is frequently upregulated during tumorigenesis. The binding of type I collagen to its receptors on tumor cells promotes tumor cell proliferation, epithelial-mesenchymal transition and metastasis. Type I collagen also regulates the efficacy of tumor therapies, such as chemotherapy, radiotherapy and immunotherapy. Furthermore, type I collagen fragments are diagnostic markers of metastatic tumors and have prognostic value. Inhibition of type I collagen synthesis has been reported to have antitumor effects in animal models. However, collagen has also been shown to possess antitumor activity. Therefore, the roles that type I collagen plays in tumor biology are complex and tumor type-dependent. In this review, we discuss the expression and regulation of synthesis of type I collagen, as well as the role upregulated type I collagen plays in various stages of cancer progression. We also discuss the role of collagen in tumor therapy. Finally, we highlight several recent approaches targeting type I collagen for cancer treatment.

Nanoplateletsomes restrain metastatic tumor formation through decoy and active targeting in a preclinical mouse model

Platelets buoy up cancer metastasis via arresting cancer cells, enhancing their adhesion, and facilitating their extravasation through the vasculature. When deprived of intracellular and granular contents, platelet decoys could prevent metastatic tumor formation. Inspired by these, we developed nanoplatesomes by fusing platelet membranes with lipid membranes (P-Lipo) to restrain metastatic tumor formation more efficiently. It was shown nanoplateletsomes bound with circulating tumor cells (CTC) efficiently, interfered with CTC arrest by vessel endothelial cells, CTC extravasation through endothelial layers, and epithelial-mesenchymal transition of tumor cells as nanodecoys. More importantly, in the mouse breast tumor metastasis model, nanoplateletsomes could decrease CTC survival in the blood and counteract metastatic tumor growth efficiently by inhibiting the inflammation and suppressing CTC escape. Therefore, nanoplatelesomes might usher in a new avenue to suppress lung metastasis.

Фенотипическое разнообразие макрофагов при раке яичников

Фенотипическое разнообразие макрофагов при раке яичников

TGFβ-induced expression of long noncoding lincRNA Platr18 controls breast cancer axonogenesis.

Metastasis is the leading driver of cancer-related death. Tumor cell plasticity associated with the epithelial-mesenchymal transition (EMT), an embryonic program also observed in carcinomas, has been proposed to explain the colonization of distant organs by the primary tumor cells. Many studies have established correlations between EMT marker expression in the primary tumor and metastasis in vivo. However, the longstanding model of EMT-transitioned cells disseminating to secondary sites is still actively debated and hybrid states are presently considered as more relevant during tumor progression and metastasis. Here, we describe an unexplored role of EMT on the tumor microenvironment by controlling tumor innervation. Using in vitro and in vivo breast tumor progression models, we demonstrate that TGFβ-mediated tumor cell EMT triggers the expression of the embryonic LincRNA Platr18 those elevated expression controls the expression of the axon guidance protein semaphorin-4F and other neuron-related molecules such as IGSF11/VSIG-3. Platr18/Sema4F axis silencing abrogates axonogenesis and attenuates metastasis. Our observations suggest that EMT-transitioned cells are also locally required in the primary tumor to support distant dissemination by promoting axonogenesis, a biological process known for its role in metastatic progression of breast cancer.

Overexpression of 15-Hydroxyprostaglandin Dehydrogenase Inhibits A549 Lung Adenocarcinoma Cell Growth via Inducing Cell Cycle Arrest and Inhibiting Epithelial-Mesenchymal Transition.

PurposeLung cancer is one of the most commonly diagnosed cancer as well as the leading cause of cancer-related mortality worldwide, among which lung adenocarcinoma (LUAD) is the most frequent form of lung cancer. Previous studies have shown that 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the oxidation of prostaglandins to reduce their biological activities and behaves as a tumor suppressor in various cancers. Thus, we aimed to systematically examine the effects of 15-PGDH overexpression on cellular processes in lung adenocarcinoma cells.MethodsThe stable 15-PGDH-overexpressing A549 cell line was constructed using lentivirus particles. CCK-8 assay was used to determine the cell proliferation rate and sensitivity to cisplatin. Tandem mass tag (TMT)-based quantitative proteomic analysis was used to identify differentially expressed proteins between control and 15-PGDH-overexpression cells. The cell cycle was determined by a flow cytometer. The expression levels of mesenchymal and epithelial markers were measured using Western blotting. Wound healing and transwell assays were used to detect the cell migration and cell invasion ability, respectively.ResultsAnalysis of datasets in The Cancer Genome Atlas revealed that the PGDH gene expression level in the lung adenocarcinoma tissues was significantly lower than that in the pericarcinous tissues. 15-PGDH overexpression in A549 cells reduced cell proliferation rate. Quantitative proteomics revealed that 15-PGDH overexpression inhibited PI3K/AKT/mTOR signaling pathway, which is a signaling pathway driving tumor cell growth and epithelial-mesenchymal transition (EMT) process. In addition, both cell cycle and DNA repair-related proteins were down-regulated in 15-PGDH overexpressed cells. 15-PGDH overexpression induced G1/S cell cycle arrest and increased susceptibility to DNA damaging reagent cisplatin. Importantly, overexpression of 15-PGDH inhibited EMT process with the downregulation of β-catenin and Snail-1 as well as upregulation of E-cadherin and ZO-1.Conclusion15-PGDH is a tumor suppressor in lung cancer and may serve as a potential therapeutic target to prevent lung adenocarcinoma.

NR2F2 controls malignant squamous cell carcinoma state by promoting stemness and invasion and repressing differentiation.

The nongenetic mechanisms required to sustain malignant tumor state are poorly understood. During the transition from benign tumors to malignant carcinoma, tumor cells need to repress differentiation and acquire invasive features. Using transcriptional profiling of cancer stem cells from benign tumors and malignant skin squamous cell carcinoma (SCC), we identified the nuclear receptor NR2F2 as uniquely expressed in malignant SCC. Using genetic gain of function and loss of function in vivo, we show that NR2F2 is essential for promoting the malignant tumor state by controlling tumor stemness and maintenance in mouse and human SCC. We demonstrate that NR2F2 promotes tumor cell proliferation, epithelial-mesenchymal transition and invasive features, while repressing tumor differentiation and immune cell infiltration by regulating a common transcriptional program in mouse and human SCCs. Altogether, we identify NR2F2 as a key regulator of malignant cancer stem cell functions that promotes tumor renewal and restricts differentiation to sustain a malignant tumor state.

CircRNA circ_0000554 promotes ovarian cancer invasion and proliferation by regulating miR-567.

Circular RNAs (circRNAs) indicated potential modulating effects in tumor development. However, the specific role of circ_0000554 in ovarian tumor remains unknown. We found that circ_0000554 was overexpressed in ovarian tumor specimens and cells. Forced expression of circ_0000554 promoted cell growth, invasion, and epithelial to mesenchymal transition (EMT). We illustrated that miR-567 was downregulated in ovarian tumor specimens and cells. circ_0000554 was negatively correlated with miR-567 in ovarian tumor specimens. circ_0000554 sponged miR-567 expression in ovarian tumor. RIP assay showed that elevated expression of miR-567 could be enriched with circ_0000554. Luciferase reporter assay indicated that luciferase intensity was inhibited after treated with miR-567 mimic; however, the luciferase value of mut type was not decreased. Elevated expression of circ_0000554 suppressed miR-567 expression in HO8910 cell. circ_0000554 promoted ovarian tumor cell growth, invasion, and EMT via sponging miR-567. It suggested that circ_0000554 represent a potential therapy target for ovarian tumor.

Suspension state and shear stress enhance breast tumor cells EMT through YAP by microRNA-29b.

Except for biochemical effects, suspension state (Sus) is proved to induce epithelial-mesenchymal transition (EMT) of circulating tumor cells (CTCs) mechanically. However, the difference between the effects of the mechanical microenvironment in capillaries (simplified as shear stress (SS) and Sus) and single Sus on EMT is unclear, nor the underlying mechanism. Here, breast tumor cells (BTCs) were loaded with Sus and SS to mimic the situation of CTCs stimulated by these two kinds of mechanics. It was demonstrated that the EMT of BTCs was enhanced by Sus and SS and the mechanotransductor yes-associated protein (YAP) was partially cytoplasmic stored with microRNA (miR)-29b decreased, which was detected by miR sequencing. Though it couldn't possess a feedback regulation, YAP promoted miR-29b expression and posttranscriptionally regulated BTCs EMT through miR-29b, where transforming growth factor β involved. Analysis of clinical database showed that high miR-29b expression was beneficial to high survival rate stabilizing its role of tumor suppressor. This study discovers the mechanism that Sus and SS promote BTCs EMT by YAP through miR-29b posttranscriptionally and highlight the potential of YAP and miR-29b in tumor therapy. The combination of suspension state and shear stress promotes transforming growth factor β involved epithelial-mesenchymal transition by yes-associated protein through microRNA-29b.

The Non-Coding RNAs Inducing Drug Resistance in Ovarian Cancer: A New Perspective for Understanding Drug Resistance.

Ovarian cancer, a common malignant tumor, is one of the primary causes of cancer-related deaths in women. Systemic chemotherapy with platinum-based compounds or taxanes is the first-line treatment for ovarian cancer. However, resistance to these chemotherapeutic drugs worsens the prognosis. The underlying mechanism of chemotherapeutic resistance in ovarian cancer remains unclear. Non-coding RNAs, including long non-coding RNAs, microRNAs, and circular RNAs, have been implicated in the development of drug resistance. Abnormally expressed non-coding RNAs can promote ovarian cancer resistance by inducing apoptosis inhibition, protective autophagy, abnormal tumor cell proliferation, epithelial-mesenchymal transition, abnormal glycolysis, drug efflux, and cancer cell stemness. This review summarizes the role of non-coding RNAs in the development of chemotherapeutic resistance in ovarian cancer, including their mechanisms, targets, and potential signaling pathways. This will facilitate the development of novel chemotherapeutic agents that can target these non-coding RNAs and improve ovarian cancer treatment.

Wnt pathway-related three-mRNA clinical outcome signature in bladder urothelial carcinoma: computational biology and experimental analyses

BackgroundThe Wnt signaling pathway is core to the growth of bladder tumors. Epithelial-to-mesenchymal transition (EMT) is significant for bladder tumor metastasis. Nevertheless, the relationship between the Wnt signaling pathway, outcomes of bladder cancer (BLCA), and the specific mechanisms driving immune infiltration have not been studied.MethodsWe obtained Wnt pathway-related gene mRNA and clinicopathological data from the Cancer Genome Atlas (TCGA). We obtained 34 genes that were greatly correlated with outcome using univariate Cox regression analysis and conducted a completely randomized data t-test to perform clinical staging. According to the single-sample gene set enrichment analysis (ssGSEA), the weighted correlation network analysis (WGCNA) was applied to identify relevant biological functions. Various subtypes were identified using consensus cluster analysis. Univariate Cox regression and least absolute shrinkage sum selection operator–Cox regression algorithm analysis were conducted on TCGA and Gene Expression Omnibus data to identify risk characteristics. The Kaplan–Meier method and receiver running feature curves were adopted to calculate overall survival. Single-sample gene set enrichment analysis (ssGSEA) was adopted for the assessment of the degree of immune infiltration. Then, we demonstrated the relationship between PPP2CB and EMT function in two cell lines.ResultsThirty-four Wnt signaling pathway-related genes were risk factors for BLCA outcome, and their expression levels differed by clinical stage. The co-expression of WGCNA showed the relationship between the Wnt signaling pathway and biological functions and was closely associated with EMT. We divided BLCA patients into two subtypes using consensus clustering. Survival curves and clinical analysis showed that the Wnt pathway enriched group had worse outcomes. The Wnt signature showed the significance of the outcome for MAPK10, PPP2CB, and RAC3. Based on these genes, the degree of immune infiltration was evaluated. Cell function experiments suggested that PPP2CB drives the proliferation and migration of BLCA cells.ConclusionWe found that Wnt signaling pathway-related genes can be used as prognostic risk factors for BLCA, and the Wnt signaling pathway is a cancer-promoting signaling pathway associated with EMT. We identified three critical genes: MAPK10, RAC3, and PPP2CB. The genes in these three Wnt signaling pathways are associated with tumor cell EMT and immune cell infiltration. The most important finding was that these three genes were independent prognostic factors for BLCA.

WNT7B represses epithelial-mesenchymal transition and stem-like properties in bladder urothelial carcinoma

BackgroundRecurrence and metastasis are the major problems of bladder urothelial carcinoma, which mainly attribute to tumor cell stemness, epithelial-mesenchymal transition (EMT) and chemoresistance. MethodsTCGA database was interrogated for gene mRNA expression in bladder urothelial carcinoma samples. CCLE database was interrogated for gene mRNA expression in bladder cancer cell lines. The correlation between two genes was analyzed by Pearson statistics. 37 human bladder urothelial carcinoma specimens were adopted for immunohistochemistry. Bladder cancer cells RT4, J82, and UM-UC-3 were used to carry out loss and gain of function studies. Kaplan-Meier method was performed to analyze the overall survival. FindingsWNT7B is downregulated in high-grade bladder urothelial carcinomas. Low WNT7B expression is associated with unfavorable prognosis. Loss and gain of function studies showed that WNT7B inhibits bladder urothelial carcinoma cell EMT, stem-like properties and chemoresistance. FZD5, a specific receptor for WNT7B, mediates WNT7B signaling. ELF3 is a downstream component of WNT7B signaling, which transcriptionally modulates NOTCH1, a tumor suppressor in bladder urothelial carcinoma. InterpretationThese data demonstrate that WNT7B/FZD5-ELF3-NOTCH1 signaling functions as a tumor-suppressing pathway in bladder urothelial carcinoma.

MicroRNAs Implications in the Onset, Diagnosis, and Prognosis of Osteosarcoma.

Osteosarcoma (OS) is a primary bone malignancy, which has a high incidence in children and adolescents. The affected cells and tissues show the properties of drug-resistance and the prognosis remains poor in OS; therefore, there is an essential need for novel therapeutic approaches. MicroRNAs (miRNAs) expression pattern has been established to be involved in the pathogenesis of OS. miRNAs are small non-coding RNA molecules, which negatively regulate gene expression at the post-transcriptional level. There are copious miRNAs that have a critical role in the onset of the disease, modulation of disease progression, and response to treatment. At the moment, the recently launched version 3.0 of Human MicroRNA Disease Database (HMDD v3.0) reports that 194 miRNAs are dysregulated in OS that might be involved in proliferation, migration, invasion, and epithelial-mesenchymal transition of tumor cells. The balance between oncogene and tumor suppressor miRNAs has vital importance in the final fate of the cell behaviors in OS. Additionally, networks of miRNAs may act in concert to induce oncogenic or tumor-suppressing properties during the initiation or the progression of OS. Up or down-regulation of these miRNAs affect the status of the disease during or after therapy. To date, over 40 miRNAs have been identified in OS disease that possess oncogenic or tumor-suppressing properties, and treatment approaches are trying to establish a proper level of such miRNAs in favor of OS therapy. The role of miRNAs involved in the pathogenesis of OS and their therapeutic potential are the reference points in this review article.

Circulating tumor cells and circulating cancer stem cells and their detection by the method of flow cytometry

This review describes the circulating cancer stem cells (CCSCs) and circulating tumor cells (CTCs). CCSCs are one of the main initiators of recurrent cancer and thus make them an important target for the development of new treatment methods. CTCs are relatively new biomarkers for the early diagnosis of metastasis. CTCs provide doctors with valuable information about each stages of cancer treatments: diagnostic of early-stage disease, early detection of recurrent cancer, the efficiency of chemotherapy, and makes it possible to select an individual sensitive drug.The most informative and frequently used markers for the detection of CSCs and CSCs were described. The mechanism of two models of tumor formation is considered: clonal and hierarchical. The known mechanisms of epithelial-mesenchymal transition of tumor cells are described. The most widely used specific cell surface markers for the detection and isolation of CTCs and CCSCs are described. The efficiency of a sensitive high-precision method of multicolor flow cytometry using specific fluorescent dye-labeled monoclonal antibodies for the detection of CCSCs and CTCs in the blood of cancer patients is analyzed. Detection of CTCs and CCSCs provides important information for the early diagnosis of metastasis and open a possibility to personalized treatment, and to monitoring of all stages cancers.

Psychologic Stress Drives Progression of Malignant Tumors via DRD2/HIF1α Signaling.

Although it is established that the sustained psychologic stress conditions under which patients with tumors often reside accelerates malignant progression of tumors, the molecular mechanism behind this association is unclear. In this work, the effect of psychologic stress on tumor progression was verified using a stress-stimulated tumor-bearing mouse model (Str-tumor). Both D2 dopamine receptor (DRD2) and hypoxia-inducible factor-1α (HIF1α) were highly expressed in the nucleus of Str-tumors. Treatment with trifluoperazine (TFP), a DRD2 inhibitor, elicited better antitumor effects in Str-tumors than the control group. These results indicate that DRD2 may mediate stress-induced malignant tumor progression. DRD2 interacted with von Hippel-Lindau (VHL) in the nucleus, and competitive binding of DRD2 and HIF1α to VHL resulted in reduced ubiquitination-mediated degradation of HIF1α, enhancing the epithelial-mesenchymal transition of tumor cells. TFP acted as an interface inhibitor between DRD2 and VHL to promote the degradation of HIF1α. In conclusion, DRD2 may promote the progression of malignant tumors induced by psychologic stress via activation of the oxygen-independent HIF1α pathway, and TFP may serve as a therapeutic strategy for stress management in patients with cancer. SIGNIFICANCE: This work identifies DRD2 regulation of HIF1α as a mechanism underlying the progression of malignant tumors stimulated by psychologic stress and suggests that DRD2 inhibition can mitigate these stress conditions in patients.See related commentary by Bernabé, p. 5144.

Antitumor effects of AZD2014, a dual mTORC1/2 inhibitor, against human hepatocellular carcinoma xenograft in nude mice

To investigate the antitumor effects of AZD2014 (a dual mTORC1/2 inhibitor) against human hepatocellular carcinoma (HCC) xenograft in mice. HCCLM3 cells were injected subcutaneously in the right flank of nude mice, and when the tumors were macroscopic, the mice were randomized into 2 groups for daily intraperitoneal injection of AZD2014 (5 mg/kg, n=5) or vehicle (5 mL/kg, n=5) for 24 days. Tumor growth was assessed using calipers every 4 days and the tumor growth curve was drawn. After the final injection, the mice were euthanized and the tumors were dissected for measuring tumor weight and histopathological analysis with HE staining. Immunohistochemical staining was used to detect the expressions of Ki-67, cleaved caspase-3, CD31, and the epithelial-mesenchymal transition (EMT)-related proteins (Ecadherin, N-cadherin, and vimentin) in the tumor tissue. Daily treatment with AZD2014 significantly suppressed HCC growth as compared with the control group. HE staining showed significantly increased tumor necrosis in AZD2014-treated mice. AZD2014 treatment inhibited tumor cell proliferation, angiogenesis and EMT progression as shown by decreased expressions of Ki-67, CD31, N-cadherin, and vimentin and increased expression of E-cadherin in the tumor tissue, and significantly promoted tumor cell apoptosis as shown by an increased expression of cleaved caspase-3 in AZD2014-treated mice. AZD2014 is a highly potent antitumor agent for HCC in nude mice bearing HCC xenografts. AZD2014 can effectively inhibit tumor proliferation, angiogenesis and EMT progression and induce tumor cell necrosis and apoptosis.

The Regulatory Role of PRRX1 in Cancer Epithelial-Mesenchymal Transition.

PRRX1 (paired related homeobox 1), a member of the paired homeobox family, exhibits an important role in tumor. It is closely correlated to the occurrence of epithelial-mesenchymal transition (EMT). PRRX1 is an important transcription factor regulating EMT and plays an important role in tumor progression. In the process of tumor metastasis, PRRX1 mainly regulates the occurrence of EMT in tumor cells through TGF-β signaling pathway, Wnt/β-catenin signaling pathway and Notch signaling pathway. PRRX1 is not only closely related to the tumor cell stemness but also involved in miRNA regulation of EMT. Therefore, PRRX1 may be a target for inhibiting the proliferation, metastasis and stemness of tumor cells. The current review provides a systemic profile of the regulatory role of PRRX1 in cancer epithelial-mesenchymal transition.

New Molecular Mechanisms and Clinical Impact of circRNAs in Human Cancer.

Simple SummaryCircular RNAs (circRNAs) belong to a new class of non-coding RNAs implicated in cellular physiological functions but also in the evolution of various human pathologies. Due to their circular shape, circRNAs are resistant to degradation by exonuclease activity, making them more stable than linear RNAs. Several findings reported that circRNAs are aberrantly modulated in human cancer tissues, thus affecting carcinogenesis and metastatization. We aim to report the most recent and relevant results about novel circRNA functions and molecular regulation, to dissert about their role as reliable cancer biomarkers, and to hypothesize their contribution to multiple hallmarks of cancer.Next generation RNA sequencing techniques, implemented in the recent years, have allowed us to identify circular RNAs (circRNAs), covalently closed loop structures resulting in RNA molecules that are more stable than linear RNAs. This class of non-coding RNA is emerging to be involved in a variety of cell functions during development, differentiation, and in many diseases, including cancer. Among the described biological activities, circRNAs have been implicated in microRNA (miRNA) sequestration, modulation of protein–protein interactions and regulation of mRNA transcription. In human cancer, circRNAs were implicated in the control of oncogenic activities such as tumor cell proliferation, epithelial-mesenchymal transition, invasion, metastasis and chemoresistance. The most widely described mechanism of action of circRNAs is their ability to act as competing endogenous RNAs (ceRNAs) for miRNAs, lncRNAs and mRNAs, thus impacting along their axis, despite the fact that a variety of additional mechanisms of action are emerging, representing an open and expanding field of study. Furthermore, research is currently focusing on understanding the possible implications of circRNAs in diagnostics, prognosis prediction, effectiveness of therapies and, eventually, therapeutic intervention in human cancer. The purpose of this review is to discuss new knowledge on the mechanisms of circRNA action, beyond ceRNA, their impact on human cancer and to dissect their potential value as biomarkers and therapeutic targets.