Malignant Properties Of Cancer Cells Research Articles

The tryptophan-kynurenine pathway in immunomodulation and cancer metastasis.

The activation of the kynurenine pathway in cancer progression and metastasis through immunomodulatory pathways has drawn attention to the potential for kynurenine pathway inhibition. The activation of the kynurenine pathway, which results in the production of kynurenine metabolites through the degradation of tryptophan, promotes the development of intrinsically malignant properties in cancer cells while facilitating tumour immune escape. In addition, kynurenine metabolites act as biologically active substances to promote cancer development and metastasis. A literature review was conducted to investigate the role of the tryptophan-kynurenine pathway in immunomodulation and cancer metastasis. Evidence suggests that several enzymes and metabolites implicated in the kynurenine pathway are overexpressed in various cancers. As such, the tryptophan pathway represents a promising target for cancer treatment. However, downstream signalling pathways, including aryl hydrocarbon receptor activation, have previously induced diverse biological effects in various malignancies, which resulted in either the promotion or the inhibition of metastasis. As a result, a thorough investigation of the kynurenine pathway and its regulatory mechanisms is necessary in order to properly comprehend the effects of kynurenine pathway activation involved in cancer development and metastasis.

Induction of lysophosphatidic acid (LPA) receptor-mediated signaling regulates cell motility and survival to anticancer drugs in cancer cells treated with hydrogen peroxide.

Hydrogen peroxide (H2O2) is one of reactive oxygen species (ROS) and promotes malignant properties of cancer cells. Lysophosphatidic acid (LPA) signaling via LPA receptor (LPA1 to LPA6) regulates a variety of cellular functions, such as cell growth, migration and differentiation. This study aimed to evaluate the effects of LPA receptors on the cell motility and survival to anticancer drugs by H2O2 in colon cancer DLD-1cells. To obtain H2O2 treated (DLD- H2O2) cells, cells were maintained in culture medium containing H2O2 (60μM) for 2 months. LPAR2 and LPAR4 gene expressions were markedly elevated in DLD-H2O2 cells. The cell motility of DLD-H2O2 cells was significantly lower than that of DLD-1cells. DLD-H2O2 cell motility was suppressed by LPA2 knockdown and stimulated by LPA4 knockdown. The cell survival rates to fluorouracil (5-FU), irinotecan (CPT-11) and oxaliplatin (L-OHP) of DLD-H2O2 cells were significantly higher than those of DLD-1cells. The cell survival rate to 5-FU of DLD-H2O2 cells was decreased by LPA2 knockdown. Conversely, LPA4 knockdown enhanced the cell survival rate to 5-FU of DLD-H2O2 cells. In the tumor microenvironment, high levels of H2O2 production are observed under hypoxic conditions. The cell survival rate to 5-FU of DLD-H2O2 cells cultured at 1% O2 was significantly higher than that of DLD-1cells cultured at 1% O2, correlating with LPAR2 gene expression. The present results suggest that the induction of LPA receptor-mediated signaling plays an important role in regulating cellular functions of DLD-1cells treated with H2O2.

LPA receptor-mediated signaling regulates cell motility and survival to anticancer drug of pancreatic cancer cells under glucose-deprived and hypoxic conditions

In tumor microenvironment, cancer cells can adapt to low conditions of nutrients and oxygen. Lysophosphatidic acid (LPA) receptor-mediated signaling is involved in the promotion of malignant properties in cancer cells. In the present study, to examine the roles of LPA receptors in the regulation of cell motility and survival to cisplatin (CDDP) of pancreatic cancer PANC-1 cells under glucose-deprived and hypoxic conditions, cells were cultured in 4500 mg/L high glucose (HG)-DMEM, 500 mg/L middle glucose (MG)-DMEM and 100 mg/L low glucose (LG)-DMEM at 21% and 1% O2. The expression levels of LPAR1 and LPAR2 genes in cells cultured in MG-DMEM and LG-DMEM were significantly elevated, compared with HG-DMEM cells. The cell motility and survival rate to CDDP of cells cultured in MG-DMEM and LG-DMEM were significantly lower than those of cells cultured in HG-DMEM. The cell survival to CDDP was enhanced by LPA1 knockdown and suppressed by LPA2 knockdown. Under hypoxic conditions (1% O2), LPAR1, LPAR2 and LPAR3 expressions were markedly higher in cells cultured in MG-DMEM and LG-DMEM than in cells cultured in HG-DMEM. The cell survival rates to CDDP of cells cultured in MG-DMEM and LG-DMEM were elevated in comparison with HG-DMEM. The cell survival to CDDP was reduced by LPA3 knockdown. These results suggest that LPA receptor-mediated signaling is involved in the regulation of malignant properties of PANC-1 cells under glucose-deprived and hypoxic conditions.

FOXA2 suppresses PKM2 transcription and affects the Wnt/β-catenin activity to block aerobic glycolysis in thyroid carcinoma.

Aerobic glycolysis is critical for the energy metabolism of cancer cells. This study focuses on the regulation of forkhead box A2 (FOXA2) on pyruvate kinase M2 (PKM2) and their effects on the glycolytic activity and malignant phenotype of thyroid carcinoma (THCA) cells. By analysing four Gene Expression Omnibus datasets and querying bioinformatics systems, we obtained FOXA2 as a poorly expressed transcription factor in THCA. Later, we validated decreased mRNA and protein levels of FOXA2 in THCA cells by quantitative polymerase chain reaction and western blot assays. FOXA2 upregulation in THCA cells suppressed the glucose uptake and lactate production, and it reduced the extracellular acidification rate, but increased the oxygen consumption rate of cells. Meanwhile, the FOXA2 overexpression blocked the proliferation and mobility, and the tumourigenic activity of cancer cells. The chromatin immunoprecipitation and luciferase assays showed that FOXA2 bound to PKM2 promoter and suppressed the transcription of PKM2, which was highly expressed in THCA cells. Further upregulation of PKM2 elevated the β-catenin, c-Myc and cyclin D1 levels and restored the glycolytic activity as well as the malignant properties of cancer cells. Collectively, this work reveals that FOXA2 suppresses aerobic glycolysis and progression of THCA by blocking PKM2 transcription and inactivating the Wnt/β-catenin pathway.

Biomimetic Hydrogels in the Study of Cancer Mechanobiology: Overview, Biomedical Applications, and Future Perspectives

Hydrogels are biocompatible polymers that are tunable to the system under study, allowing them to be widely used in medicine, bioprinting, tissue engineering, and biomechanics. Hydrogels are used to mimic the three-dimensional microenvironment of tissues, which is essential to understanding cell–cell interactions and intracellular signaling pathways (e.g., proliferation, apoptosis, growth, and survival). Emerging evidence suggests that the malignant properties of cancer cells depend on mechanical cues that arise from changes in their microenvironment. These mechanobiological cues include stiffness, shear stress, and pressure, and have an impact on cancer proliferation and invasion. The hydrogels can be tuned to simulate these mechanobiological tissue properties. Although interest in and research on the biomedical applications of hydrogels has increased in the past 25 years, there is still much to learn about the development of biomimetic hydrogels and their potential applications in biomedical and clinical settings. This review highlights the application of hydrogels in developing pre-clinical cancer models and their potential for translation to human disease with a focus on reviewing the utility of such models in studying glioblastoma progression.

Abstract 143: Novel HSP40 or J domain protein inhibitors that deplete misfolded mutant p53

Abstract Background: Accumulation of oncogenic mutant p53 (mutp53) greatly contributes to cancer progression. Heat shock protein 40 (HSP40), also known as J-domain proteins (JDPs), has been implicated in stabilization of misfolded mutp53. Specifically, knockdown of DNAJA1, a member of HSP40/JDPs, results in degradation of mainly misfolded mutp53, leading to inhibition of tumor progression. Since no DNAJA1 inhibitors are currently available in clinics, these findings prompted us to identify potential DNAJA1 inhibitors which can induce mutp53 degradation. Methods/Design: An in-silico docking study was performed for binding of the DNAJA1 J-domain to compounds in zinc data base, which identified compound Number7-3. Further analysis suggests three critical amino acids in DNAJA1 for the binding, including Y7, K44, and Q47. Results: Eighteen commercially available analogs of Number7-3 were further examined. Of these, a compound, namely A11, had the strongest activity to deplete both DNAJA1 and misfolded mutp53. A11 reduced protein levels of misfolded mutp53 in concentration- and time-dependent manners without affecting mRNA levels of DNAJA1 and mutp53. Importantly, A11 showed minimal effects on the levels of wild-type p53 and DNA contact mutp53. Treatment of cells expressing misfolded mutp53 with A11 resulted in reduced filopodia formation and cell migration, which was not observed in cells lacking DNAJA1. Moreover, protein levels of a triple mutant DNAJA1 (Y7A/K44A/Q47A) were not altered by A11. Intriguingly, A11 reduced protein levels of several other HSP40/JDPs. Conclusions: Our study, for the first time, has identified a small compound that depletes DNAJA1, leading to reduced levels of misfolded mutp53 and inhibited malignant properties of cancer cells. Citation Format: Tomoo Iwakuma, Shigeto Nishikawa, Atsushi Kaida, Atul Ranjan, Alejandro Parrales, Mohamed A. Alalem, David K. Johnson. Novel HSP40 or J domain protein inhibitors that deplete misfolded mutant p53 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 143.

Effects of lysophosphatidic acid (LPA) signaling via LPA receptors on cellular functions associated with ATP reduction in osteosarcoma cells treated with ethidium bromide.

Lysophosphatidic acid (LPA) signaling via LPA receptors (LPA1 to LPA6) exhibits a variety of malignant properties in cancer cells. Intracellular ATP depletion leads to the development of necrosis and apoptosis. The present study aimed to evaluate the effects of LPA receptor-mediated signaling on the regulation of cancer cell functions associated with ATP reduction. Long-term ethidium bromide (EtBr) treated (MG63-EtBr) cells were established from osteosarcoma MG-63 cells. The intracellular ATP levels of MG63-EtBr cells were significantly lower than that of MG-63 cells. LPAR2, LPAR3, LPAR4 and LPAR6 gene expressions were elevated in MG63-EtBr cells. The cell motile and invasive activities of MG63-EtBr cells were markedly higher than those of MG-63 cells. The cell motile activity of MG-63 cells was increased by LPA4 and LPA6 knockdowns. In cell survival assay, cells were treated with cisplatin (CDDP) every 24h for 3 days. The cell survival to CDDP of MG63-EtBr cells was lower than that of MG-63 cells. LPA2 knockdown decreased the cell survival to CDDP of MG-63 cells. The cell survival to CDDP of MG-63 cells was inhibited by (2S)-OMPT (LPA3 agonist). Moreover, the cell survival to CDDP of MG-63 cells was enhanced by LPA4 and LPA6 knockdowns. These results indicate that LPA signaling via LPA receptors is involved in the regulation of cellular functions associated with ATP reduction in MG-63 cells treated with EtBr.

Biosynthesis and Biological Significances of LacdiNAc Group on N- and O-Glycans in Human Cancer Cells.

An increasing number of studies have shown that the disaccharide GalNAcβ1→4GlcNAc (LacdiNAc) group bound to N- and O-glycans in glycoproteins is expressed in a variety of mammalian cells. Biosynthesis of the LacdiNAc group was well studied, and two β4-N-acetylgalactosaminyltransferases, β4GalNAcT3 and β4GalNAcT4, have been shown to transfer N-acetylgalactosamine (GalNAc) to N-acetylglucosamine (GlcNAc) of N- and O-glycans in a β-1,4-linkage. The LacdiNAc group is often sialylated, sulfated, and/or fucosylated, and the LacdiNAc group, with or without these modifications, is recognized by receptors and lectins and is thus involved in the regulation of several biological phenomena, such as cell differentiation. The occurrences of the LacdiNAc group and the β4GalNAcTs appear to be tissue specific and are closely associated with the tumor progression or regression, indicating that they will be potent diagnostic markers of particular cancers, such as prostate cancer. It has been demonstrated that the expression of the LacdiNAc group on N-glycans of cell surface glycoproteins including β1-integrin is involved in the modulation of their protein functions, thus affecting cellular invasion and other malignant properties of cancer cells. The biological roles of the LacdiNAc group in cancer cells have not been fully understood. However, the re-expression of the LacdiNAc group on N-glycans, which is lost in breast cancer cells by transfection of the β4GalNAcT4 gene, brings about the partial restoration of normal properties and subsequent suppression of malignant phenotypes of the cells. Therefore, elucidation of the biological roles of the LacdiNAc group in glycoproteins will lead to the suppression of breast cancers.

Ganglioside GD2 Enhances the Malignant Phenotypes of Melanoma Cells by Cooperating with Integrins.

Gangliosides have been considered to modulate cell signals in the microdomain of the cell membrane, lipid/rafts, or glycolipid-enriched microdomain/rafts (GEM/rafts). In particular, cancer-associated gangliosides were reported to enhance the malignant properties of cancer cells. In fact, GD2-positive (GD2+) cells showed increased proliferation, invasion, and adhesion, compared with GD2-negative (GD2−) cells. However, the precise mechanisms by which gangliosides regulate cell signaling in GEM/rafts are not well understood. In order to analyze the roles of ganglioside GD2 in the malignant properties of melanoma cells, we searched for GD2-associating molecules on the cell membrane using the enzyme-mediated activation of radical sources combined with mass spectrometry, and integrin β1 was identified as a representative GD2-associating molecule. Then, we showed the physical association of GD2 and integrin β1 by immunoprecipitation/immunoblotting. Close localization was also shown by immuno-cytostaining and the proximity ligation assay. During cell adhesion, GD2+ cells showed multiple phospho-tyrosine bands, i.e., the epithelial growth factor receptor and focal adhesion kinase. The knockdown of integrin β1 revealed that the increased malignant phenotypes in GD2+ cells were clearly cancelled. Furthermore, the phosphor-tyrosine bands detected during the adhesion of GD2+ cells almost completely disappeared after the knockdown of integrin β1. Finally, immunoblotting to examine the intracellular distribution of integrins during cell adhesion revealed that large amounts of integrin β1 were localized in GEM/raft fractions in GD2+ cells before and just after cell adhesion, with the majority being localized in the non-raft fractions in GD2− cells. All these results suggest that GD2 and integrin β1 cooperate in GEM/rafts, leading to enhanced malignant phenotypes of melanomas.

An Update on Molecular Pathways Regulating Vasculogenic Mimicry in Human Osteosarcoma and Their Role in Canine Oncology.

Canine tumors are valuable comparative models for human counterparts, especially to explore novel biomarkers and to understand pathways and processes involved in metastasis. Vasculogenic mimicry (VM) is a unique property of malignant cancer cells which promote metastasis. Thus, it represents an opportunity to investigate both the molecular mechanisms and the therapeutic targets of a crucial phenotypic malignant switch. Although this biological process has been largely investigated in different human cancer types, including osteosarcoma, it is still largely unknown in veterinary pathology, where it has been mainly explored in canine mammary tumors. The presence of VM in human osteosarcoma is associated with poor clinical outcome, reduced patient survival, and increased risk of metastasis and it shares the main pathways involved in other type of human tumors. This review illustrates the main findings concerning the VM process in human osteosarcoma, search for the related current knowledge in canine pathology and oncology, and potential involvement of multiple pathways in VM formation, in order to provide a basis for future investigations on VM in canine tumors.

Inhibition of miR-144-3p exacerbates non-small cell lung cancer progression by targeting CEP55.

Increasing evidence has indicated that microRNA dysregulation is closely related to the occurrence and development of cancers. Herein, we investigated the relationship between miR-144-3p and CEP55 expression. We then evaluated the association between miR-144-3p and CEP55 expression and proliferation, invasion and apoptosis of non-small cell lung cancer (NSCLC) cells. Real-time quantitative PCR results revealed that CEP55 was over-expressed whereas miR-144-3p was under-expressed in NSCLC tissues. CCK-8 assay, wound healing assay, and flow cytometry further revealed that overexpression of miR-144-3p significantly inhibited proliferation and migration, but promoted apoptosis of A549 cells. Conversely, inhibition of miR-144-3p promoted proliferation and migration but suppressed apoptosis of H460 cells. Dual-luciferase reporter assay revealed that miR-144-3p modulated malignant properties of cancer cells by targeting CEP55. Overexpression of CEP55 partially blocked the inhibitory effect of miR-144-3p on proliferation and migration of A549 cells and induced apoptosis of A549 cells. CEP55 knockdown modulated the increase in proliferation and migration and the decrease in apoptosis of H460 cells following miR-144-3p inhibition. These findings demonstrated that miR-144-3p suppresses NSCLC development by inhibiting CEP55 expression.

Inhibition of the invasion and metastasis of mammary carcinoma cells by NBD peptide targeting S100A4 via the suppression of the Sp1/MMP‑14 axis.

A synthetic peptide that blocks the interaction between the metastasis-enhancing calcium-binding protein, S100A4, and its effector protein, methionine aminopeptidase 2 (MetAP2) (the NBD peptide), was previously demonstrated to inhibit the angiogenesis of endothelial cells, leading to the regression of human prostate cancer in a xenograft model. However, the effects of the NBD peptide on the malignant properties of cancer cells that express S100A4 remain to be elucidated. The present study demonstrates that the NBD peptide inhibits the invasiveness and metastasis of highly metastatic human mammary carcinoma cells. The introduction of the peptide into MDA-MB-231 variant cells resulted in the suppression of matrix degradation in a gelatin invadopodia assay and invasiveness in a Matrigel invasion assay. In line with these results, the peptide significantly downregulated the expression of matrix metalloproteinase (MMP)-14 (MT1-MMP). Mechanistic analysis of the downregulation of MMP-14 revealed the suppression of the expression of the transcription factor, specificity protein 1 (Sp1), but not that of nuclear factor (NF)-κB, early growth response 1 (EGR1) or ELK3, all of which were reported to be involved in transcriptional regulation of the MMP-14 gene. At the same time, evidence suggested that the NBD peptide also suppressed Sp1 and MMP-14 expression levels in MDA-MB-468 cells. Importantly, the intravenous administration of the NBD peptide encapsulated in liposomes inhibited pulmonary metastasis from mammary gland tumors in mice with xeno-graft tumors. These results indicate that the NBD peptide can suppress malignant tumor growth through the suppression of the Sp1/MMP-14 axis. Taken together, these results reveal that the NBD peptide acts on not only endothelial cells, but also on tumor cells in an integrated manner, suggesting that the peptide may prove to be a promising cancer therapeutic peptide drug.

Sphingosine 1-Phosphate Signaling and Metabolism in Chemoprevention and Chemoresistance in Colon Cancer.

Colorectal carcinoma (CRC) is the leading cause of cancer-related deaths worldwide. Despite advances in prevention and treatment modalities for CRC, rapidly developing resistance to chemotherapy limits its effectiveness. For that reason, it is important to better understand the mechanisms that undergird the process of chemoresistance to enable design of novel anticancer agents specifically targeting malignant properties of cancer cells. Over recent decades, bioactive sphingolipid species have come under the spotlight for their recognized role in cancer development and progression, and the evidence has surfaced to support their role as regulators of anti-cancer drug resistance. Colon cancer is characterized by a shift in sphingolipid balance that favors the production and accumulation of oncogenic species such as sphingosine 1-phosphate (S1P). S1P is known to govern the processes that facilitate cancer cell growth and progression including proliferation, survival, migration, invasion and inflammation. In this review paper, we will give a comprehensive overview of current literature findings on the molecular mechanisms by which S1P turnover, transport and signaling via receptor-dependent and independent pathways shape colon cancer cell behavior and influence treatment outcome in colon cancer. Combining available modulators of S1P metabolism and signaling with standard chemotherapy drugs could provide a rational approach to achieve enhanced therapeutic response, diminish chemoresistance development and improve the survival outcome in CRC patients.

Lysophosphatidic acid receptor-2 (LPA2)-mediated signaling enhances chemoresistance in melanoma cells treated with anticancer drugs.

Lysophosphatidic acid (LPA) signaling through LPA receptors (LPA1 to LPA6) regulates a variety of malignant properties in cancer cells. Recently, we show that LPA2 expression is elevated by long-term cisplatin (CDDP) treatment in melanoma A375 cells. In the present study, we investigated whether LPA2-mediated signaling is involved in the modulation of chemoresistance in A375 cells. In cell survival assay, cells were treated with CDDP and dacarbazine (DTIC) every 24h for 2days. The cell survival rates to CDDP and DTIC were markedly increased by an LPA2 agonist, GRI-977143. To validate the effects of LPA2 on cell survival, LPA2 knockdown cells were generated from A375 cells. The cell survival rates elevated by GRI-977143 were suppressed by LPA2 knockdown. To evaluate the roles of LPA2-mediated signaling in cell survival, cells were pretreated with a Gi protein inhibitor, pertussis toxin (PTX). In the presence of GRI-977143, the cell survival rates to CDDP and DTIC were significantly lower in PTX-treated cells than in untreated cells. In addition, pretreatment of an adenylyl cyclase inhibitor, SQ22536, increased the cell survival of A375 cells treated with CDDP and DTIC. These results suggest that LPA2-mediated signaling plays an important role in the enhancement of chemoresistance of A375 cells treated with anticancer drugs.

Regulation of cell survival through free fatty acid receptor 1 (FFA1) and FFA4 induced by endothelial cells in osteosarcoma cells

Free fatty acid receptor 1 (FFA1) and FFA4 belong to a family of free fatty acid (FFA) receptors. FFA1- and FFA4-mediated signaling regulates a variety of malignant properties in cancer cells. It is known that stromal cells in the tumor microenvironment promote tumor progression. In the present study, to assess the roles of FFA1 and FFA4 in cellular functions modulated by endothelial cells, highly migratory MG63-CR7(F2) cells were generated from osteosarcoma MG-63 cells, using endothelial F2 cell supernatants. Expression levels of FFAR1 and FFAR4 genes in MG63-CR7(F2) cells were significantly higher than those of MG-63 cells. In cell survival assay, cells were treated with cisplatin (CDDP) every 24 h for 2 days. The cell survival rate of MG-63 cells was significantly elevated by an FFA1 agonist TUG-770 as well as an FFA4 agonist TUG-891. Moreover, the cell survival rate of MG63-CR7(F2) cells was higher than that of MG-63 cells in the presence of TUG-770 or TUG-891, correlating with FFAR1 and FFAR4 expression levels. To validate the effects of FFA1 and FFA4 on cell survival to CDDP, FFA1 and FFA4 knockdown cell were generated from MG-63 cells. The cell survival rate of MG-63 cells was markedly inhibited by FFA1 or FFA4 knockdown. These results suggest that FFA1 and FFA4 may play an important role in the modulation of cellular functions by endothelial cells in osteosarcoma cells.

Characterization of the immune microenvironment in brain metastases from different solid tumors.

BackgroundBrain metastases are one of the most common intracranial neoplasms. Increasing evidence have indicated that systemic immunotherapy may provide long‐term benefits for brain metastases. Herein, we presented the results of an immune oncology panel RNA sequencing platform for patients with brain metastases from different primary sites.MethodsWe investigated 25 samples of human brain metastases from lung cancer (n = 12), breast cancer (n = 6), and colorectal cancer (n = 7). Besides, 13 paired samples of adjacent noncancerous brain tissue (10 from patients with lung cancer and 3 from patients with breast cancer) were collected as controls. By comparing the brain metastases and paired samples of adjacent noncancerous brain tissue from 13 patients, we detected three upregulated and six downregulated genes, representing the malignant properties of cancer cells and increased immune infiltration in the microenvironment. Next, we profiled the immune‐related genes in brain metastases from three primary cancer types.ResultsA group of genes were significantly overexpressed in the microenvironment of brain metastases from lung cancer, covering the checkpoint pathways, lymphocyte infiltration, and TCR‐coexpression. Especially, immune checkpoint molecules, PD‐L1, PD‐L2, and IDO1 were expressed at higher levels in brain metastases from lung cancer than those from the other two cancer types.ConclusionsThis study presents an immune landscape of brain metastases from different cancer types. With high RNA expression levels of PD‐1/PD‐L1 axis and immune infiltration in brain metastases, it would be worthwhile to explore the efficacy of immune checkpoint blockade for lung cancer patients with intracranial metastases.

MicroRNA-493-5p-mediated repression of the MYCN oncogene inhibits hepatic cancer cell growth and invasion.

Primary hepatic tumors mainly include hepatocellular carcinoma (HCC), which is one of the most frequent causes of cancer‐related deaths worldwide. Thus far, HCC prognosis has remained extremely poor given the lack of effective treatments. Numerous studies have described the roles played by microRNAs (miRNAs) in cancer progression and the potential of these small noncoding RNAs for diagnostic or therapeutic applications. The current consensus supports the idea that direct repression of a wide range of oncogenes by a single key miRNA could critically affect the malignant properties of cancer cells in a synergistic manner. In this study, we aimed to investigate the oncogenes controlled by miR‐493‐5p, a major tumor suppressor miRNA that inactivates miR‐483‐3p oncomir in hepatic cancer cells. Using global gene expression analysis, we highlighted a set of candidate genes potentially regulated by miR‐493‐5p. In particular, the canonical MYCN protooncogene (MYCN) appeared to be an attractive target of miR‐493‐5p given its significant inhibition through 3′‐UTR targeting in miR‐493‐5p‐rescued HCC cells. We showed that MYCN was overexpressed in liver cancer cell lines and clinical samples from HCC patients. Notably, MYCN expression levels were inversely correlated with miR‐493‐5p in tumor tissues. We confirmed that MYCN knockdown mimicked the anticancer effect of miR‐493‐5p by inhibiting HCC cell growth and invasion, whereas MYCN rescue hindered miR‐493‐5p activity. In summary, miR‐493‐5p is a pivotal miRNA that modulates various oncogenes after its reexpression in liver cancer cells, suggesting that tumor suppressor miRNAs with a large spectrum of action could provide valuable tools for miRNA replacement therapies.

LPA5-mediated signaling induced by endothelial cells and anticancer drug regulates cellular functions of osteosarcoma cells

Lysophosphatidic acid (LPA) signaling via LPA receptors (LPA1 to LPA6) regulates a variety of malignant properties of cancer cells. It is known that endothelial cells promote tumor progression and chemoresistance. The present study aimed to investigate the roles of LPA5 in cellular functions modulated by endothelial cells and anticancer drug in osteosarcoma cells. Human osteosarcoma MG-63 cells were maintained in endothelial F2 cell supernatants. After culturing for 3 months, MG63-F2 cells were established. LPAR5 expression level in MG63-F2 cells was significantly elevated, compared with MG-63 cells. The cell motile activity of MG63-F2 cells was markedly higher than that of MG-63 cells. To validate the effects of LPA5 on cell motile activity, LPA5 knockdown cells were generated from MG-63 cells. The cell motile activity of MG-63 cells was inhibited by LPA5 knockdown. The cell survival to cisplatin (CDDP) was reduced in MG-63 cells treated with LPA. In the presence of LPA, the cell survival rate was significantly lower in MG63-F2 cells than MG-63 cells, correlating with LPAR5 expression. LPA5 knockdown cells indicated the high cell survival rate to CDDP. Moreover, LPAR5 expression level was increased in the long-term CDDP treated MG63-C cells. The cell survival to CDDP of MG63-C cells was enhanced by LPA5 knockdown. These results suggest that cellular functions are regulated through LPA5-mediatd signaling induced by endothelial cells and CDDP in MG-63 cells.

Zinc dysregulation in cancers and its potential as a therapeutic target.

Zinc is an essential element and serves as a structural or catalytic component in many proteins. Two families of transporters are involved in maintaining cellular zinc homeostasis: the ZIP (SLC39A) family that facilitates zinc influx into the cytoplasm, and the ZnT (SLC30A) family that facilitates zinc efflux from the cytoplasm. Zinc dyshomeostasis caused by the dysfunction of zinc transporters can contribute to the initiation or progression of various cancers, including prostate cancer, breast cancer, and pancreatic cancer. In addition, intracellular zinc fluctuations lead to the disturbance of certain signaling pathways involved in the malignant properties of cancer cells. This review briefly summarizes our current understanding of zinc dyshomeostasis in cancer, and discusses the potential roles of zinc or zinc transporters in cancer therapy.

The role of YWHAZ in cancer: A maze of opportunities and challenges.

YWHAZ (also named 14-3-3ζ) is a central hub protein for many signal transduction pathways and plays a significant role in tumor progression. Accumulating evidences have demonstrated that YWHAZ is frequently up-regulated in multiple types of cancers and acts as an oncogene in a wide range of cell activities including cell growth, cell cycle, apoptosis, migration, and invasion. Moreover, YWHAZ was reported to be regulated by microRNAs (miRNAs) or long non-coding RNAs and exerted its malignant functions by targeting downstream molecules like protein kinase, apoptosis proteins, and metastasis-related molecules. Additionally, YWHAZ may be a potential biomarker of diagnosis, prognosis and chemoresistance in several cancers. Targeting YWHAZ by siRNA, shRNA or miRNA was reported to have great help in suppressing malignant properties of cancer cells. In this review, we perform literature and bioinformatics analysis to reveal the oncogenic role and molecular mechanism of YWHAZ in cancer, and discuss the potential clinical applications of YWHAZ concerning diagnosis, prognosis, and therapy in malignant tumors.