Malignant Phenotype Of Cancer Cells Research Articles

APE1 shRNA-loaded cancer stem cell-derived extracellular vesicles reverse Erlotinib resistance in non-small cell lung cancer via the IL-6/STAT3 signalling.

ObjectiveApurinic endonuclease 1 (APE1) has been suggested as an oncogene of lung tumours and our bioinformatics analysis identified the association between Erlotinib resistance and interleukin‐6 (IL‐6). Thus, we performed this work to delineate the mechanistic actions of APE1/IL‐6 signalling in Erlotinib resistance of non‐small cell lung cancer (NSCLC).MethodsWe selected human NSCLC cell lines HCC827 and PC9 to establish Erlotinib‐resistant HCC827R and PC9R cells. Cancer stem cells (CSCs) were isolated from Erlotinib‐sensitive HCC827P and PC9P cells (PCSCs) and from HCC827R and PC9R cells (RCSCs). Further, extracellular vesicles (EVs) were separated from PCSCs (PCSC‐EVs) and RCSCs (RCSC‐EVs) and co‐cultured with RCSCs with or without short hairpin RNA (shRNA)‐targeting APE1 (APE1 shRNA) transduction. In addition, functional assays were conducted to determine the effect of APE1 shRNA on malignant phenotypes of cancer cells in vitro and in vivo and the activation of IL‐6/STAT3 signalling.ResultsIt was found that NSCLC cells could internalize both RCSC‐EVs and PCSC‐EVs. RCSC‐EVs augmented the resistance of NSCLC cells to Erlotinib. The overexpression of APE1 occurred in NSCLC tissues, and IL‐6 was enriched in serum samples of patients with NSCLC. APE1 shRNA was demonstrated to restrict the Erlotinib resistance of NSCLC cells by inactivating the IL‐6/STAT3 signalling. Additionally, shAPE1‐loaded RCSC‐EVs suppressed the Erlotinib resistance of NSCLC via the IL‐6/STAT3 axis both in vitro and in vivo, as reflected by impeded malignant phenotypes and xenograft tumour formation.ConclusionsCollectively, these data indicate that APE1 confers Erlotinib resistance by activating the IL‐6/STAT3 signalling, suggesting targeting APE1 as a possible therapeutic target in Erlotinib‐resistant NSCLC.

DCAF12 promotes apoptosis and inhibits NF-κB activation by acting as an endogenous antagonist of IAPs

Members of the Inhibitor of Apoptosis Protein (IAP) family are essential for cell survival and appear to neutralize the cell death machinery by binding pro-apoptotic caspases. dcaf12 was recently identified as an apoptosis regulator in Drosophila. However, the underlying molecular mechanisms are unknown. Here we revealed that human DCAF12 homolog binds multiple IAPs, including XIAP, cIAP1, cIAP2, and BRUCE, through recognition of BIR domains in IAPs. The pro-apoptotic function of DCAF12 is dependent on its capacity to bind IAPs. In response to apoptotic stimuli, DCAF12 translocates from the nucleus to the cytoplasm, where it blocks the interaction between XIAP and pro-apoptotic caspases to facilitate caspase activation and apoptosis execution. Similarly, DCAF12 suppresses NF-κB activation in an IAP binding-dependent manner. Moreover, DCAF12 acts as a tumor suppressor to restrict the malignant phenotypes of cancer cells. Together, our results suggest that DCAF12 is an evolutionarily conserved IAP antagonist.

SEC14L3 plays a tumor-suppressive role in breast cancer through a Wnt/β-catenin-related way

Breast cancer, the most prevalent malignancy in women, is also the leading cause of cancer-related deaths in women worldwide. The activation of the Wnt pathway plays a pivotal role in the metastatic abilities of breast cancer. In this study, IL1F6, MRGPRX1, and SEC14L3 were significantly correlated to breast cancer patients'overall survival based on TCGA-BRCA dataset. Although IL1F6, MRGPRX1 and SEC14L3 high expression were associated with better survival in breast cancer patients, SEC14L3 had the biggest survival benefit for breast cancer; therefore, SEC14L3 was selected for the subsequent investigation. SEC14L3 mRNA expression and protein levels within breast cancer cell lines decreased compared with normal human breast epithelial cells. Overexpressing SEC14L3 in breast cancer cells inhibited the malignant phenotypes of cancer cells, including the capacity of cells to migrate and invade. SEC14L3 overexpression decreased the levels of mesenchymal markers, whereas SEC14L3 knockdown facilitated the malignant behaviors of breast cancer cells. SEC14L3 overexpression also inhibited Wnt/β-catenin activation. The Wnt agonist strengthened the malignant phenotypes of breast cancer cells; moreover, the anti-tumor effects of SEC14L3 overexpression were partially attenuated by the Wnt agonist. Conclusively, SEC14L3, which is underexpressed in breast cancer cells and tissues, could play a tumor-suppressive role in a Wnt/β-catenin-related way.

Distinct Roles of m5C RNA Methyltransferase NSUN2 in Major Gynecologic Cancers.

RNA methylation has recently emerged as an important category of epigenetic modifications, which plays diverse physiopathological roles in various cancers. Recent studies have confirmed the presence of 5-methylcytosine (m5C) modification on mammalian mRNAs, mainly modified by NOP2/Sun RNA methyltransferase family member 2 (NSUN2), but little is known about the underlying functions of m5C. Gynecologic cancers are malignancies starting from women’s reproductive organs. The prevalence of gynecologic cancers leads to a massive economic burden and public health concern. In this study, we investigated the potential biological functions of NSUN2 in common gynecologic cancers including cervical cancer, ovarian cancer, and endometrial cancer. Remarkably, distinct scenarios were found. The levels of NSUN2 did not show alteration in endometrial cancer, and in ovarian cancer, depletion of upregulated NSUN2 did not reduce carcinogenesis in cancer cells, suggesting that the upregulated NSUN2 might be an incidental effect. On the contrary, NSUN2 played a role in tumorigenesis of cervical cancer; depletion of upregulated NSUN2 notably inhibited migration and invasion of cancer cells, and only wild-type but not catalytically inactive NSUN2 rescued these malignant phenotypes of cancer cells. Mechanistically, NSUN2 promoted migration and invasion by leading to m5C methylation on keratin 13 (KRT13) transcripts, and methylated KRT13 transcripts would be recognized and stabilized by an m5C reader, Y-box binding protein 1 (YBX1). Collectively, these results not only displayed the nature of diversity among human malignancies, but also demonstrated a novel NSUN2-dependent m5C-YBX1-KRT13 oncogenic regulatory pathway.

N6-Methyladenosine-regulated LINC00675 suppress the proliferation, migration and invasion of breast cancer cells via inhibiting miR-513b-5p

ABSTRACT Breast cancer (BC) is the most common cancer among women. LINC00675 and miR-513b-5p has been reported to be abnormally expressed in multiple types of cancers and modulate malignant phenotypes of cancer cells. However, to date, the functional role and underlying regulatory mechanism of LINC00675 and miR-513b-5p in BC remains largely unknown. Here, we found that LINC00675 was significantly downregulated in BC tissues and cell lines. Decrease of LINC00675 expression associated with higher tumor grade, lymphovascular invasion and shorter survival in BC patients. Functional experiments demonstrated that overexpression of LINC00675 suppressed BC cell proliferation, migration and invasion, whereas depletion of LINC00675 exerted opposite effects. Mechanistically, LINC00675 functioned as a competing endogenous RNA (ceRNA) to interact with miR-513b-5p and suppress its expression. Moreover, METTL3 increased the m6A methylation of LINC00675, which enhanced the association between LINC00675 and miR-513b-5p. Collectively, the central findings of our study suggest that LINC00675 represses BC progression through the inhibition of miR-513b-5p in a m6A-dependent manner.

Long non-coding RNA DUXAP8 elevates RCN2 expression and facilitates cell malignant behaviors and angiogenesis in cervical cancer via sponging miR-1297

BackgroundCervical cancer (CC) endangers women’s health in the world range. Accumulating studies have revealed the crucial regulatory role of long non-coding RNAs (lncRNAs) in multiple malignancies, including CC. Our study aimed to explore the role of lncRNA double homeobox A pseudogene 8 (DUXAP8) in cervical carcinogenesis.MethodsGene expressions in CC were assessed by RT-qPCR. Function experiments and tube formation assays were performed to evaluate the role of DUXAP8 in CC cells. Subcellular fractionation and FISH assays were conducted to determine the subcellular location of DUXAP8. Luciferase reporter, RNA pull down and RIP assays were conducted to investigate the mechanism of DUXAP8.ResultsDUXAP8 was notably upregulated in CC cells. Downregulation of DUXAP8 repressed cell malignant behaviors and angiogenesis in CC. Mechanically, DUXAP8 boosted the expression of reticulocalbin-2 (RCN2) through relieving the binding of miR-1297 to RCN2 3’-UTR. Moreover, miR-1297 inhibition and RCN2 overexpression could counteract the inhibitory effects of DUXAP8 knockdown on the malignant phenotypes of CC cells. Besides, enhanced RCN2 expression restored the tumor growth in vivo that was inhibited by DUXAP8 repression.ConclusionsDUXAP8 promotes malignant behaviors in CC cells via regulating miR-1297/RCN2 axis.Graphical

Circ_0069718 promotes the progression of breast cancer by up-regulating NFIB through sequestering miR-590-5p.

Researches indicate that circular RNAs are dysregulated in breast cancer (BC) and play a critical role in regulating the malignant phenotype of cancer cells. Herein, the goal of this work was to investigate the role and mechanism of circ_0069718 in BC development. Levels of genes and proteins were detected by quantitative real-time polymerase chain reaction and western blot. In vitro experiments were performed using cell counting kit-8 assay, colony formation assay, EdU (5-ethynyl-2'-deoxyuridine) assay, flow cytometry, western blot, and transwell assay, respectively. The dual-luciferase reporter and RNA immunoprecipitation assays were used to identify the target relationship between miR-590-5p and circ_0069718 or nuclear factor I/B (NFIB). In vivo experiments were conducted using Xenograft model in mice. Circ_0069718 was up-regulated in BC tissues and cells. Knockdown of circ_0069718 suppressed BC cell apoptosis, migration, and invasion in vitro effectively. Mechanistically, circ_0069718 directly targeted miR-590-5p to up-regulate its target NFIB. Rescue experiments showed that miR-590-5p inhibition reversed the inhibitory effects of circ_0069718 knockdown on BC cell-aggressive oncogenic phenotypes; moreover, miR-590-5p re-expression restrained BC cell proliferation and mobility, which were abolished by NFIB up-regulation. Besides that, circ_0069718 silencing hindered tumor growth via miR-590-5p/NFIB axis in vivo. Circ_0069718 promotes BC progression by up-regulating NFIB through sequestering miR-590-5p, suggesting a potential therapeutic strategy in BC.

Mesenchymal Stem Cell-derived Extracellular Vesicles Transmitting MicroRNA-34a-5p Suppress Tumorigenesis of Colorectal Cancer Through c-MYC/DNMT3a/PTEN Axis

Mesenchymal stem cell–derived extracellular vesicles (MSC-EV) can transport microRNAs (miRNAs) into colorectal cancer (CRC) cells, thus to inhibit the malignant phenotype of cancer cells. Whether MSC-EV could deliver miR-34a-5p to suppress CRC development was surveyed through the research. miR-34a-5p, c-MYC, DNA methyltransferase 3a (DNMT3a), and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression were measured in CRC tissues and cell lines. miR-34a-5p and c-MYC expression were altered by transfection in HCT-116 cells. MSC-EV were transfected with miR-34a-5p- and c-MYC-related oligonucleotides and co-cultured with HCT-116 cells. HCT-116 cell growth after treatment was observed. Furthermore, the functional roles of miR-34a-5p and c-MYC were explored in vivo. The combined interactions of miR-34a-5p/c-MYC/DNMT3a/PTEN axis were assessed. miR-34a-5p and PTEN were downregulated while c-MYC and DNMT3a were upregulated in CRC. Depletion of miR-34a-5p drove while that of c-MYC restricted CRC cell growth. MSC-EV retarded CRC progression. Moreover, MSC-EV carrying overexpressed miR-34a-5p or depleted c-MYC further disrupted CRC cell progression. miR-34a-5p targeted c-MYC to regulate DNMT3a and PTEN. c-MYC overexpression abrogated EV-derived miR-34a-5p upregulation-induced effects on CRC. Restoring miR-34a-5p or depleting c-MYC in MSC-EV limited CRC tumor formation. MSC-EV-derived miR-34a-5p depresses CRC development through modulating the binding of c-MYC to DNMT3a and epigenetically regulating PTEN.

Apolipoprotein C-II induces EMT to promote gastric cancer peritoneal metastasis via PI3K/AKT/mTOR pathway.

BackgroundPeritoneal metastasis (PM) occurs frequently in patients with gastric cancer (GC) and confers poor survival. Lipid metabolism acts as a non‐negligible regulator in epithelial–mesenchymal transition (EMT), which is crucial for the metastasis of GC. As apolipoprotein C2 (APOC2) is a key activator of lipoprotein lipase for triglyceride metabolism, the exact mechanism of APOC2 remains largely unknown in GC.MethodsTandem mass tags identified differentially expressed proteins between human PM and GC tissues, and showed that APOC2 overexpressed in PM tissues, which was further confirmed by immunoblotting, immunohistochemistry, and ELISA. Global gene expression changes were identified in APOC2 knockdown cells via RNA‐sequencing. The role of APOC2 in lipid metabolism of GC cells was assessed via the Seahorse XF analyzer and lipid staining assays. The biological role of APOC2 in GC cells was determined by 3D Spheroid invasion, apoptosis, colony formation, wound healing, transwell assay, and mouse models. The interaction between APOC2 and CD36 was analyzed by co‐immunoprecipitation and biolayer interferometry. The underlying mechanisms were investigated using western blot technique.ResultsAPOC2 overexpressed in GC PM tissues. Upregulation of APOC2 correlated with a poor prognosis in GC patients. APOC2 promoted GC cell invasion, migration, and proliferation via CD36‐mediated PI3K/AKT/mTOR signaling activation. Furthermore, APOC2‐CD36 axis upregulated EMT markers of GC cells via increasing the phosphorylation of PI3K, AKT, and mTOR. Knockdown either APOC2 or CD36 inhibited the malignant phenotype of cancer cells, and delayed GC PM progression in murine GC models.ConclusionAPOC2 cooperates with CD36 to induce EMT to promote GC PM via PI3K/AKT/mTOR pathway. APOC2‐CD36 axis may be a potential target for the treatment of aggressive GC.

LINC00922 promotes the proliferation, migration, invasion and EMT process of liver cancer cells by regulating miR-424-5p/ARK5.

AMPK-related protein kinase 5 (ARK5) promotes the deterioration of hepatocellular carcinoma (HCC). From the perspective of lncRNA-miRNA-mRNA, this study explored in-depth the intervention mechanism of ARK5. The binding relationship between miR-424-5p and two genes (LINC00922 and ARK5) were analyzed by Bioinformatics and dual-luciferase experiments. After clinical sample collection, the expressions of miR-424-5p, LINC00922 and ARK5 in HCC tissues were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). The correlation between LINC00922, miR-424-5p, and ARK5 in HCC tissues was analyzed by Pearson correlation. The influences of miR-424-5p, LINC00922 and ARK5 on the basic functions (viability, migration and invasion) of cancer cells were detected by cell counting kit-8, wound healing, and Transwell experiments, and their regulatory effects on related genes, as well as their relationship, were tested by qRT-PCR and Western blot. MiR-424-5p was low expressed, whereas LINC00922 and ARK5 were high expressed in HCC tissues. MiR-424-5p was negatively associated with LINC00922 and ARK5 that was positively associated with LINC00922. Interestingly, LINC00922 partially shared an identical binding site of miR-424-5p with ARK5. LINC00922 its overexpression partially offset the inhibitory effect of miR-424-5p on cancer cell functions. ARK5 silencing repressed the malignant phenotype of cancer cells and inhibited the expressions of epithelial-to-mesenchymal transition (EMT)-related molecules (Vimentin, Snail and N-Cadherin). However, these effects were partially neutralized by miR-424-5p inhibitors. LINC00922 increases the cell viability, migration, invasion and EMT process of HCC cells by regulating the miR-424-5p/ARK5 axis, and thus may serve as a potential target for targeted therapy.

Cancer-Associated Glycosphingolipids as Tumor Markers and Targets for Cancer Immunotherapy.

Aberrant expression of glycosphingolipids is a hallmark of cancer cells and is associated with their malignant properties. Disialylated gangliosides GD2 and GD3 are considered as markers of neuroectoderm origin in tumors, whereas fucosyl-GM1 is expressed in very few normal tissues but overexpressed in a variety of cancers, especially in small cell lung carcinoma. These gangliosides are absent in most normal adult tissues, making them targets of interest in immuno-oncology. Passive and active immunotherapy strategies have been developed, and have shown promising results in clinical trials. In this review, we summarized the current knowledge on GD2, GD3, and fucosyl-GM1 expression in health and cancer, their biosynthesis pathways in the Golgi apparatus, and their biological roles. We described how their overexpression can affect intracellular signaling pathways, increasing the malignant phenotypes of cancer cells, including their metastatic potential and invasiveness. Finally, the different strategies used to target these tumor-associated gangliosides for immunotherapy were discussed, including the use and development of monoclonal antibodies, vaccines, immune system modulators, and immune effector-cell therapy, with a special focus on adoptive cellular therapy with T cells engineered to express chimeric antigen receptors.

Methylation of microRNA-338-5p by EED promotes METTL3-mediated translation of oncogene CDCP1 in gastric cancer.

Unmasking the complex regulatory pathways that mediate the malignant phenotypes of cancer cells can provide novel targets for therapies that could limit the recurrence and metastasis of gastric cancer (GC). Herein, we intended to clarify the role of embryonic ectoderm development protein (EED), microRNA-228-5p (miR-338-5p), methyltransferase like 3 (METTL3) and CUB domain containing protein 1 (CDCP1) in GC. Differentially expressed miRNAs and their target genes were extracted by in silico analysis. The studies revealed high expression of EED in GC tissues and cell lines and it high expression in GC patients was shown to be associated with poor prognosis. The chromatin immunoprecipitation assay identified that EED methylated miR-338-5p to inhibit its expression. EED knockdown could restrain the proliferative and invasive abilities of GC cells by inducing miR-338-5p. Furthermore, miR-338-5p targeted m6A methylase METTL3, while METTL3 amplified the translation of CDCP1 via m6A activity which led to accelerated proliferation and invasion of GC cells. Moreover, in vivo experiments validated that EED promoted the progression of GC through mediating the miR-338-5p/METTL3/CDCP1 axis. Collectively, EED downregulated miR-338-5p through histone methylation, which in turn impaired miR-338-5p-dependent METTL3 inhibition and enhanced CDCP1 translation, therefore contributing to the development of GC.

The noncoding RNAs SNORD50A and SNORD50B-mediated TRIM21-GMPS interaction promotes the growth of p53 wild-type breast cancers by degrading p53

Small nucleolar RNA SNORD50A and SNORD50B (SNORD50A/B) has been reported to be recurrently deleted and function as a putative tumor suppressor in different types of cancer by binding to and suppressing the activity of the KRAS oncoproteins. Its deletion correlates with poorer patient survival. However, in this study, we surprisingly found that SNORD50A/B loss predicted a better survival in breast cancer patients carrying wild-type p53. Functional studies showed that SNORD50A/B deletion strongly inhibited the proliferation, migration, invasion and tumorigenic potential, and induced cell cycle arrest and apoptosis in p53 wild-type breast cancer cells, while exerted the opposite effects in p53 mutated breast cancer cells. This was also supported by ectopically expressing SNORD50A/B in both p53 wild-type and mutated breast cancer cells. Mechanistically, SNORD50A/B clearly enhances the interaction between E3 ubiquitin ligase TRIM21 and its substrate GMPS by forming a complex among them, thereby promoting GMPS ubiquitination and its subsequent cytoplasmic sequestration. SNORD50A/B deletion in p53 wild-type breast cancer cells will release GMPS and induce the translocation of GMPS into the nucleus, where GMPS can recruit USP7 and form a complex with p53, thereby decreasing p53 ubiquitination, stabilizing p53 proteins, and inhibiting malignant phenotypes of cancer cells. Altogether, the present study first reports that SNORD50A/B plays an oncogenic role in p53 wild-type breast cancers by mediating TRIM21-GMPS interaction.

TGF-β-induced cell motility requires downregulation of ARHGAPs to sustain Rac1 activity

Transforming growth factor-β (TGF-β) signaling promotes cancer progression. In particular, the epithelial–mesenchymal transition (EMT) induced by TGF-β is considered crucial to the malignant phenotype of cancer cells. Here, we report that the EMT-associated cellular responses induced by TGF-β are mediated by distinct signaling pathways that diverge at Smad3. By expressing chimeric Smad1/Smad3 proteins in SMAD3 knockout A549 cells, we found that the β4 region in the Smad3 MH1 domain is essential for TGF-β-induced cell motility, but is not essential for other EMT-associated responses including epithelial marker downregulation. TGF-β was previously reported to enhance cell motility by activating Rac1 via phosphoinositide 3-kinase. Intriguingly, TGF-β-dependent signaling mediated by Smad3's β4 region causes the downregulation of multiple mRNAs that encode GTPase activating proteins that target Rac1 (ARHGAPs), thereby attenuating Rac1 inactivation. Therefore, two independent pathways downstream of TGF-β type I receptor contribute cooperatively to sustained Rac1 activation, thereby leading to enhanced cell motility.

Alpha-fetoprotein Promotes the Malignant Phenotype of Hepatocellular Carcinoma Cells: the Drugs Resistance Origination

Hepatocellular carcinoma (HCC) has a high increase, recurrence and mortality rate, but the signs of pathogenesis are not clear. At the time of diagnosis, most patients were advanced stage and missed the optimal period of surgical resection. Pharmacotherapy is the primary choice in this period, but the efficacy of anticancer drugs is poor and the patient survival rate is low. Drugs resistance is the primary cause of the poor efficacy of anticancer drugs. HCC cells have innate drugs resistance and acquired drugs resistance, and understanding the drugs resistance mechanism of HCC cells has an important help in the treatment of HCC. Alpha fetoprotein (AFP) is a tumor-associated protein, about 70% high expression of AFP in HCC patients, and AFP has a trait to induce malignant phenotype, stimulate cancer cells with a highly aggressive, antiapoptotic, proliferated phenotype, etc. AFP can also promote HCC drugs resistance through regulating the transduction of signaling pathways and ultimately lead to drugs resistance. This review analyze AFP influences the origination of cancer stem cells, promotes malignant phenotype of cancer cells, and the mechanism that promote HCC cells drugs resistance.

Upregulated lncRNA DLX6-AS1 underpins hepatocellular carcinoma progression via the miR-513c/Cul4A/ANXA10 axis

Recent studies have illustrated the role of aberrant regulatory interactions in the mediation of malignant phenotypes of cancer cells, which could potentially provide novel therapeutic targets to limit the destructive recurrence and metastasis of hepatocellular carcinoma (HCC). Herein, we clarify the oncogenic role of the long noncoding RNA (lncRNA) distal-less homeobox 6 antisense 1 (DLX6-AS1) in HCC in vivo and in vitro. To this end, we knocked down lncRNA DLX6-AS1 and manipulated the expression of miR-513c to characterize their effects in HCC cell viability, migration, invasion, and apoptosis. Furthermore, we probed the interactions with miR-513c's target gene Cullin4A (Cul4A) and the degradation of Annexin A10 (ANXA10) protein. Our data show that lncRNA DLX6-AS1 and Cul4A were highly expressed, while miR-513c and ANXA10 were poorly expressed in HCC tissues and cells. Moreover, the silencing of lncRNA DLX6-AS1 impeded the viability, invasion, and migration of HCC cells, while stimulating cell apoptosis. Further data indicated that lncRNA DLX6-AS1 targeted and repressed miR-513c expression, where the tumor-inhibiting effects of lncRNA DLX6-AS1 silencing was achieved by elevating miR-513c expression. Importantly, the lncRNA DLX6-AS1 upregulated the expression of Cul4A through sponging of miR-513c. The silencing of Cul4A restricted the malignant phenotypes of HCC cells by repressing the ubiquitination-mediated degradation of ANXA10. In vivo experiments verified that lncRNA DLX6-AS1 promoted the progression of HCC through the miR-513c/Cul4A/ANXA10 axis. Thus, the silencing of lncRNA DLX6-AS1 impaired miR-513c-dependent Cul4A inhibition and subsequently elevated ubiquitination-mediated degradation of ANXA10, thereby preventing the occurrence and development of HCC.

STARD4 promotes breast cancer cell malignancy.

Breast cancer (BRCA) is one of the most common malignancies encountered in women worldwide. Lipid metabolism has been found to be involved in cancer progression. Steroidogenic acute regulatory protein-related lipid transfer 4 (STARD4) is an important cholesterol transporter involved in the regulatory mechanism of intracellular cholesterol homeostasis. However, to the best of our knowledge, the molecular functions of STARD4 in BRCA are unclear. Immunohistochemical staining and public dataset analysis were performed to investigate the expression levels of STARD4 in BRCA. In the present study, high expression of STARD4 was identified in BRCA samples and higher STARD4 expression was significantly associated with shorter distant metastasis-free survival time in patients with BRCA, which indicated that STARD4 may be associated with BRCA progression. Cell cytometry system Celigo® analysis, Cell Counting K-8 assays, flow cytometry, wound healing assays and transwell assays were used to investigate the effects of STARD4 knockdown on proliferation, cell cycle, apoptosis and migration in BRCA cells. Loss-of-function assays demonstrated that STARD4 acted as an oncogene to promote proliferation and cell cycle progression, while suppressing apoptosis in BRCA cells in vitro and in vivo. Furthermore, knockdown of STARD4 significantly suppressed BRCA metastasis. To assess the mechanism of action of STARD4, microarray analysis was performed following STARD4 knockdown in MDA-MB-231 cells. The data were analyzed in detail using bioinformatics, and a series of genes, including E74 like ETS transcription factor 1, cAMP responsive element binding protein 1 and p21 (RAC1) activated kinase 2, which have been previously reported to be crucial genes implicated in the malignant phenotype of cancer cells, were identified to be regulated by STARD4. Loss-of function assays demonstrated that knockdown of STARD4 suppressed BRCA proliferation and migration. These findings suggested that STARD4 had an oncogenic effect in human BRCA progression.

Systemic Regulation of Cancer Development by Neuro-Endocrine-Immune Signaling Network at Multiple Levels.

The overarching view of current tumor therapies simplifies cancer to a cell-biology problem in which neoplasms are caused solely by malignant cells and the exploration of carcinogenesis and tumor progression largely focuses on somatic mutations and other genetic abnormalities of cancer cells. The limited therapeutic response indicates that cancer is driven not only by endogenous oncogenic factors and reciprocal interactions within the tumor microenvironment, but also by complex systemic processes. Homeostasis is the fundamental premise of health, and is maintained by systemic regulation of neuro-endocrine-immune axis. Cancer is also a systemic disease that manifested by dysfunction of the nervous, endocrine, and immune systems. Multiple axes of regulation exist in cancer, including central-, organ-, and microenvironment-level manipulation. At each specific regulatory level, the tridirectional communication among the nervous, endocrine, and immune factors transmit flexible signaling to induce proliferation, invasion, reprogrammed metabolism, therapeutic resistance, and other malignant phenotypes of cancer cells, resulting in the extremely poor prognosis of this lethal disease. Understanding this coordinated signaling network will enable the development of new approaches for cancer treatment via behavioral and pharmacological interventions.

Circ_0000144 facilitates the progression of thyroid cancer via the miR‐217/AKT3 pathway

Thyroid carcinoma (TC) is the most common malignancy of the endocrine system. Circular RNA (circRNA) is vital in the regulation of tumor progression. Circ_0000144 serves as a novel oncogenic circRNA, and miR-217 is reported to inhibit the malignant phenotypes of cancer cells by targeting AKT3 in TC. The present study aimed to explore the regulatory mechanism of circ_0000144 and miR-217 in the progression of TC. Circ_0000144 expression in 32 pairs of TC tissues and different TC cell lines (including BCPAP, K1, H7H83, and TPC-1) was detected by employing a quantitative real-time polymerase chain reaction (qRT-PCR). Circ_0000144 small interfering RNA was used to establish loss-of-function models. Cell counting kit-8 (CCK-8), BrdU (5-bromo-2'-deoxyuridine) and transwell assays were utilized to verify the effects of circ_0000144 on TC cell proliferation, migration and invasion, respectively. Bioinformatics, western blotting, a luciferase reporter experiment and qRT-PCR were employed to confirm the relationships among circ_0000144, miR-217 and AKT3. Circ_0000144 expression was remarkably elevated in TC tissues (p<0.001) and TC cell lines. The elevation of circ_0000144 expression was markedly linked to tumor size (p=0.015), TNM stage (p=0.025) and lymph node metastasis (p=0.017) of the patients. Functional studies showed that knocking down circ_0000144 repressed the malignancy of TC cells. Furthermore, miR-217 was identified as a downstream target of circ_0000144; inhibition of miR-217 could reverse the effects induced by circ_0000144 knockdown. Moreover, circ_0000144 could regulate AKT3 expression by suppressing miR-217 expression. Circ_0000144 exerts a cancer-promoting effect on TC cells via the miR-217/AKT3 pathway.

The Role of Epac in Cancer Progression

Cancer continues to be a prime contributor to global mortality. Despite tremendous research efforts and major advances in cancer therapy, much remains to be learned about the underlying molecular mechanisms of this debilitating disease. A better understanding of the key signaling events driving the malignant phenotype of cancer cells may help identify new pharmaco-targets. Cyclic adenosine 3′,5′-monophosphate (cAMP) modulates a plethora of biological processes, including those that are characteristic of malignant cells. Over the years, most cAMP-mediated actions were attributed to the activity of its effector protein kinase A (PKA). However, studies have revealed an important role for the exchange protein activated by cAMP (Epac) as another effector mediating the actions of cAMP. In cancer, Epac appears to have a dual role in regulating cellular processes that are essential for carcinogenesis. In addition, the development of Epac modulators offered new routes to further explore the role of this cAMP effector and its downstream pathways in cancer. In this review, the potentials of Epac as an attractive target in the fight against cancer are depicted. Additionally, the role of Epac in cancer progression, namely its effect on cancer cell proliferation, migration/metastasis, and apoptosis, with the possible interaction of reactive oxygen species (ROS) in these phenomena, is discussed with emphasis on the underlying mechanisms and pathways.