Gene Summary

Gene:MTOR; mechanistic target of rapamycin kinase
Summary:The protein encoded by this gene belongs to a family of phosphatidylinositol kinase-related kinases. These kinases mediate cellular responses to stresses such as DNA damage and nutrient deprivation. This protein acts as the target for the cell-cycle arrest and immunosuppressive effects of the FKBP12-rapamycin complex. The ANGPTL7 gene is located in an intron of this gene. [provided by RefSeq, Sep 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:serine/threonine-protein kinase mTOR
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: MTOR (cancer-related)

Itoh M, Okuhashi Y, Takahashi Y, et al.
Hypoxia Up-regulates HIF Expression While Suppressing Cell Growth and NOTCH Activity in Leukaemia Cells.
Anticancer Res. 2019; 39(8):4165-4170 [PubMed] Related Publications
AIM: To examine the influence of hypoxia on the in vitro growth of leukaemia cells and the activity of signalling proteins to better understand the pathophysiology of leukaemia cells in human bone marrow.
MATERIALS AND METHODS: Six human leukaemia cell lines were cultured under normoxic or hypoxic conditions. Cell growth, recovery of clonogenic cells, and the expression and activation of various signalling proteins were examined.
RESULTS: Hypoxia suppressed cell growth and the recovery of clonogenic cells. Moreover, hypoxia up-regulated hypoxia-inducible factor (HIF) 1α and HIF2α expression while suppressing the expression and activation of NOTCH1, mechanistic target of rapamycin kinase (mTOR) activation, and nuclear factor-kappa B (NF-κB) phosphorylation.
CONCLUSION: We found that hypoxia up-regulated HIF expression while it suppressed the self-renewal capacity of leukaemia cells, NOTCH activity, and expression of its down-stream signalling molecules, which differs from previous reports mentioning that HIF activates NOTCH signalling. Our findings serve to further elucidate the in vivo pathophysiology of leukaemia cells.

Xiao B, Zhang W, Kuang Z, et al.
SOX9 promotes nasopharyngeal carcinoma cell proliferation, migration and invasion through BMP2 and mTOR signaling.
Gene. 2019; 715:144017 [PubMed] Related Publications
SRY-related high-mobility-group box 9 (SOX9) is a member of the SOX family of transcription factors. Accumulating evidence has shown that SOX9 plays a significant role in various malignancies. However, the role of SOX9 in nasopharyngeal carcinoma (NPC) remains unknown. In the present study, up-regulation of SOX9 was observed in both NPC tissues and different NPC cells. Overexpression of SOX9 promoted NPC cell proliferation, migration and invasion. Conversely, knock down of SOX9 inhibited NPC proliferation, colony formation, migration and invasion. Mechanistically, SOX9 bound directly to the promoter region of BMP2 and increased BMP2 expression. In addition, overexpression of SOX9 activated the mTOR pathway partly through BMP2. Collectively, these results identify a novel role for SOX9 as a potential therapeutic marker for the prevention and treatment of NPC.

Wu TK, Chen CH, Pan YR, et al.
Cetrimonium Bromide Inhibits Cell Migration and Invasion of Human Hepatic SK-HEP-1 Cells Through Modulating the Canonical and Non-canonical TGF-β Signaling Pathways.
Anticancer Res. 2019; 39(7):3621-3631 [PubMed] Related Publications
BACKGROUND/AIM: Cetrimonium bromide (CTAB), a quaternary ammonium surfactant, is an antiseptic agent against bacteria and fungi. However, the mechanisms by which its pharmacological actions affect epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) cells, such as adenocarcinoma in SK-HEP-1 cells, have not been investigated. We, thereby, investigated whether CTAB inhibits cellular mobility and invasiveness of human hepatic adenocarcinoma in SK-HEP-1 cells.
MATERIALS AND METHODS: SK-HEP-1 cells were treated with CTAB, and subsequent migration and invasion were measured by wound healing and transwell assays. Protein expression was detected by immunoblotting analysis.
RESULTS: Our data revealed that treatment of SK-HEP-1 cells with CTAB altered their mesenchymal spindle-like morphology. CTAB exerted inhibitory effects on the migration and invasion of SK-HEP-1 cells dose-dependently, and reduced protein levels of matrix metalloproteinase-2 (MMP-2), MMP-9, snail, slug, twist, vimentin, fibronectin, N-cadherin, Smad2, Smad3, Smad4, phosphoinositide-3-kinase (PI3K), p-PI3K, Akt, p-Akt, β-catenin, mammalian target of rapamycin (mTOR), p-mTOR, p-p70S6K, p-extracellular signal-regulated kinases (ERK)1/2, p-p38 mitogen-activated protein kinase (MAPK) and p-c-Jun N-terminal kinase (JNK), but increased protein levels of tissue inhibitor matrix metalloproteinase-1 (TIMP-1), TIMP-2, claudin-1 and p-GSK3β. Based on these observations, we suggest that CTAB not only inhibits the canonical transforming growth factor-β (TGF-β) signaling pathway though reducing SMADs (an acronym from the fusion of Caenorhabditis elegans Sma genes and the Drosophila Mad, Mothers against decapentaplegic proteins), but also restrains the non-canonical TGF-β signaling including MAPK pathways like ERK1/2, p38 MAPK, JNK and PI3K.
CONCLUSION: CTAB is involved in the suppression of TGF-β-mediated mesenchymal phenotype and could be a potent medical agent for use in controlling the migration and invasion of hepatic adenocarcinoma.

Zhihua Y, Yulin T, Yibo W, et al.
Hypoxia decreases macrophage glycolysis and M1 percentage by targeting microRNA-30c and mTOR in human gastric cancer.
Cancer Sci. 2019; 110(8):2368-2377 [PubMed] Free Access to Full Article Related Publications
Macrophages are essential inflammatory cells which regulate the features of immune reactions within tumors. Many studies have reported their regulatory roles in immunity through cytokines and cell signaling. However, relatively few studies have focused on their metabolic features and mechanisms. We aimed to determine the signaling pathway regulating cell metabolism and the mechanism related to the regulation of human tumor-associated macrophages (TAMs) in gastric cancer (GC). Tumor-infiltrated macrophages were isolated from human GC tissues using magnetic beads, gene transcription was determined by real-time PCR, protein expression was monitored using western blots, metabolites were determined using HPLC, and transcriptional regulation was analyzed by the luciferase-based reporter gene system. A significant decrease in microRNA (miR)-30c and an increase in regulated in development and DNA damage responses 1 (REDD1) were detected in human GC TAMs, the transcription of miR-30c was negatively correlated with REDD1. MicroRNA-30c expression was suppressed by hypoxia-inducible factor-1α activation and related to decreased mTOR activity as well as glycolysis in human GC TAMs. Hypoxia-regulated miR-30c downregulated REDD-1 expression by targeting its 3'UTR. Overexpression of miR-30c or restored mTOR activity in macrophages with miR-30c

Ogawa H, Kaira K, Motegi Y, et al.
Role of Amino Acid Transporter Expression as a Prognostic Marker in Patients With Surgically Resected Colorectal Cancer.
Anticancer Res. 2019; 39(5):2535-2543 [PubMed] Related Publications
BACKGROUND/AIM: L-type amino acid transporter 1 (LAT1) is highly expressed in various human cancers. However, the clinicopathological significance of LAT1 and 4F2 cell surface antigen (4F2hc) in patients with colorectal cancer (CRC) is unknown. The aim of this study was to clarify the prognostic significance of LAT1 expression in CRC patients who underwent surgical resection.
MATERIALS AND METHODS: Samples from one hundred and forty-seven patients were examined by immunohistochemistry. The expression of LAT1 and 4F2hc, and the Ki-67 labeling index were assessed using resected tumor specimens.
RESULTS: The positive expression of LAT1 and 4F2c was 80% (118/147) and 58% (86/147) (p<0.01), respectively. The expression of LAT1 was identified as an independent significant marker linked to worse prognosis in patients with CRC, and was correlated with tumor cell proliferation, tumor aggressiveness, and metastasis. Moreover, LAT1 was closely associated with the expression of 4F2hc and phosphorylation of the mTOR pathway.
CONCLUSION: LAT1 is a significant molecular marker used to predict prognosis after surgical resection of CRC patients.

Liu J, Wang T, Creighton CJ, et al.
Nat Commun. 2019; 10(1):2148 [PubMed] Free Access to Full Article Related Publications
Mechanisms of lung squamous cell carcinoma (LSCC) development are poorly understood. Here, we report that JNK1/2 activities attenuate Lkb1-deficiency-driven LSCC initiation and progression through repressing ΔNp63 signaling. In vivo Lkb1 ablation alone is sufficient to induce LSCC development by reducing MKK7 levels and JNK1/2 activities, independent of the AMPKα and mTOR pathways. JNK1/2 activities is positively regulated by MKK7 during LSCC development. Pharmaceutically elevated JNK1/2 activities abates Lkb1 dependent LSCC formation while compound mutations of Jnk1/2 and Lkb1 further accelerate LSCC progression. JNK1/2 is inactivated in a substantial proportion of human LSCC and JNK1/2 activities positively correlates with survival rates of lung, cervical and head and neck squamous cell carcinoma patients. These findings not only determine a suppressive role of the stress response regulators JNK1/2 on LSCC development by acting downstream of the key LSCC suppresser Lkb1, but also demonstrate activating JNK1/2 activities as a therapeutic approach against LSCC.

Huang E, Huang H, Guan T, et al.
Involvement of C/EBPβ-related signaling pathway in methamphetamine-induced neuronal autophagy and apoptosis.
Toxicol Lett. 2019; 312:11-21 [PubMed] Related Publications
Methamphetamine (METH) is a widely abused illicit psychoactive drug. Our previous study has shown that CCAAT-enhancer binding protein β (C/EBPβ) is an important regulator in METH-induced neuronal autophagy and apoptosis. However, the detailed molecular mechanisms underlying this process remain poorly understood. Previous studies have demonstrated that DNA damage-inducible transcript 4 (DDIT4), Trib3 (tribbles pseudo kinase 3), alpha-synuclein (α-syn) are involved in METH-induced dopaminergic neurotoxicity. We hypothesized that C/EBPβ is involved in METH-induced DDIT4-mediated neuronal autophagy and Trib3-mediated neuronal apoptosis. We tested our hypothesis by examining the effects of silencing C/EBPβ, DDIT4, Trib3 or α-syn with small interfering ribonucleic acid (siRNA) on METH-induced autophagy and apoptosis in the human neuroblastoma SH-SY5Y cells. We also measured the levels of phosphorylated tuberous sclerosis complex 2 (TSC2) protein and Parkin protein level in SH-SY5Y cells. Furthermore, we demonstrated the effect of silencing C/EBPβ on METH-caused neurotoxicity in the striatum of rats by injecting LV-shC/EBPβ lentivirus using a stereotaxic positioning system. The results showed that METH exposure increased C/EBPβ, DDIT4 protein expression. Elevated DDIT4 expression raised up p-TSC2/TSC2 protein expression ratio, inhibited mTOR signaling pathway, activating cell autophagy. We also found that METH exposure increased the expression of Trib3, α-syn, decreased the Parkin protein expression. Lowering levels of Parkin raised up α-syn expression, which initiated mitochondrial apoptosis by down-regulating anti-apoptotic Bcl-2, followed by up-regulation of pro-apoptotic Bax, resulting in translocation of cytochrome c (cyto c), an apoptogenic factor, from the mitochondria to cytoplasm and activation of caspase-dependent pathways. These findings were supported by data showing METH-induced autophagy and apoptosis was significantly inhibited by silencing C/EBPβ, DDIT4, Trib3 or α-syn, or by Parkin over-expression. Based on the present data, a novel of mechanism on METH-induced cell toxicity is proposed, METH exposure increased C/EBPβ protein expression, triggered DDIT4/TSC2/mTOR signaling pathway, and evoked Trib3/Parkin/α-syn-related mitochondrial apoptotic signaling pathway. Collectively, these results suggest that C/EBPβ plays an important role in METH-triggered autophagy and apoptosis and it may be a potential target for therapeutics in METH-caused neurotoxicity.

Mohankumar K, Li X, Sridharan S, et al.
Nuclear receptor 4A1 (NR4A1) antagonists induce ROS-dependent inhibition of mTOR signaling in endometrial cancer.
Gynecol Oncol. 2019; 154(1):218-227 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
OBJECTIVES: NR4A1 is overexpressed in many solid tumors, and the objectives of this study were to investigate the expression and functional role of this receptor in endometrial cancer cells and demonstrate that NR4A1 antagonist inhibit mTOR.
METHODS: Ishikawa and Hec-1B endometrial cells were used as models to investigate the parallel effects of NR4A1 knockdown by RNA interference (siNR4A1) and treatment with bis-indole-derived NR4A1 ligands (antagonists) on cell growth and survival by determining cell numbers and effects on Annexin V staining. Western blot analysis of whole cell lysates was used to determine effects of these treatments on expression of growth promoting, survival and apoptotic genes and mTOR signaling. Effects of NR4A1 antagonists on tumor growth were determined in athymic nude mice bearing Hec-1B cells as xenografts.
RESULTS: siNR4A1 or treatment with bis-indole-derived NR4A1 antagonists inhibited growth of endometrial cancer cells in vitro and endometrial tumors in vivo and this was accompanied by decreased expression of growth promoting and survival genes and mTOR inhibition.
CONCLUSIONS: NR4A1 exhibited pro-oncogenic activity in endometrial cells due, in part, to regulation of cell growth, survival and mTOR signaling, and all of these pathways and their associated gene products were inhibited after treatment with bis-indole-derived NR4A1 antagonists. Moreover, these compounds also blocked endometrial tumor growth in vivo demonstrating that NR4A1 is a potential novel drug target for treatment of endometrial cancer.

Aras S, Maroun MC, Song Y, et al.
Mitochondrial autoimmunity and MNRR1 in breast carcinogenesis.
BMC Cancer. 2019; 19(1):411 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
BACKGROUND: Autoantibodies function as markers of tumorigenesis and have been proposed to enhance early detection of malignancies. We recently reported, using immunoscreening of a T7 complementary DNA (cDNA) library of breast cancer (BC) proteins with sera from patients with BC, the presence of autoantibodies targeting several mitochondrial DNA (mtDNA)-encoded subunits of the electron transport chain (ETC) in complexes I, IV, and V.
METHODS: In this study, we have characterized the role of Mitochondrial-Nuclear Retrograde Regulator 1 (MNRR1, also known as CHCHD2), identified on immunoscreening, in breast carcinogenesis. We assessed the protein as well as transcript levels of MNRR1 in BC tissues and in derived cell lines representing tumors of graded aggressiveness. Mitochondrial function was also assayed and correlated with the levels of MNRR1. We studied the invasiveness of BC derived cells and the effect of MNRR1 levels on expression of genes associated with cell proliferation and migration such as Rictor and PGC-1α. Finally, we manipulated levels of MNRR1 to assess its effect on mitochondria and on some properties linked to a metastatic phenotype.
RESULTS: We identified a nuclear DNA (nDNA)-encoded mitochondrial protein, MNRR1, that was significantly associated with the diagnosis of invasive ductal carcinoma (IDC) of the breast by autoantigen microarray analysis. In focusing on the mechanism of action of MNRR1 we found that its level was nearly twice as high in malignant versus benign breast tissue and up to 18 times as high in BC cell lines compared to MCF10A control cells, suggesting a relationship to aggressive potential. Furthermore, MNRR1 affected levels of multiple genes previously associated with cancer metastasis.
CONCLUSIONS: MNRR1 regulates multiple genes that function in cell migration and cancer metastasis and is higher in cell lines derived from aggressive tumors. Since MNRR1 was identified as an autoantigen in breast carcinogenesis, the present data support our proposal that both mitochondrial autoimmunity and MNRR1 activity in particular are involved in breast carcinogenesis. Virtually all other nuclear encoded genes identified on immunoscreening of invasive BC harbor an MNRR1 binding site in their promoters, thereby placing MNRR1 upstream and potentially making it a novel marker for BC metastasis.

Hong CH, Lin SH, Lee CH
CCL21 Induces mTOR-dependent MALAT1 Expression, Leading to Cell Migration in Cutaneous T-Cell Lymphoma.
In Vivo. 2019 May-Jun; 33(3):793-800 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
BACKGROUND: Mycosis fungoides (MF) is indolent, but may disseminate to leukemia. We reported that C-C motif chemokine ligand 21 (CCL21) is associated with MF invasion and progression. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long noncoding RNA, is associated with several cancer types, however, how it interacts with CCL21 to regulate MF progression, remains unclear.
MATERIALS AND METHODS: Expression of long noncoding RNAs MALAT1, antisense noncoding RNA in the INK4 locus (ANRIL), Hox antisense intergenic RNA (HOTAIR), highly up-regulated in liver cancer RNA (HULC), and leukemia-associated non-coding insulin-like growth factor 1 receptor activator RNA 1 (LUNAR1) in tissues from MF was studied using polymerase chain reaction and RNA interference in MF cell line MyLa were used to address this question.
RESULTS: Expression of MALAT1 was selectively increased in MF tissues. C-C Chemokine receptor type 7 (CCR7) expression was found to be increased in MyLa cells. CCL21 was found not only to mediate migration, but also to enhance MALAT1 and mammalian target of rapamycin (mTOR) activation in MyLa cells. Knockdown of MALAT1 abrogated CCL21-mediated migration, but not mTOR activation. In contrast, mTOR inhibition reduced CCL21-mediated migration and MALAT1 expression.
CONCLUSION: CCL21 induced mTOR activation in MyLa cells, followed by expression of MALAT1, causing cell migration. MALAT1 and mTOR are potential therapeutic targets for MF.

Ahmed ESA, Ahmed NH, Medhat AM, et al.
Mesenchymal stem cells targeting PI3K/AKT pathway in leukemic model.
Tumour Biol. 2019; 41(4):1010428319846803 [PubMed] Related Publications
Mesenchymal stem cells have therapeutic properties that are related to their potentials for trans-differentiation, immunomodulation, anti-inflammatory, inhibitory effect on tumor proliferation, and induction of apoptosis. This study was performed to analyze the role of mesenchymal stem cells as an alternative for cellular signaling growth factors involved in the pathogenesis of leukemogenesis in rats. Treatment of rats with 7,12-dimethyl benz [a] anthracene induced leukemogenesis appeared as a significant decrease in hematological parameters with concomitant significant increase in bone marrow oxidative and inflammatory indices (transforming growth factor beta and interleukin-6) in comparison with normal groups. On the contrary, Western immunoblotting showed a significant increase in the signaling growth factors: PI3K, AKT, mTOR proteins and a significant decrease in PTEN in 7,12-dimethyl benz [a] anthracene-treated group. In addition, a significant increase in the transcript levels of B cell lymphoma-2 protein gene in the 7,12-dimethyl benz [a] anthracene group, while that of C-X-C motif chemokine receptor-4 and B cell lymphoma-2 protein associated x-protein were significantly downregulated compared to controls. Meanwhile, therapeutic mesenchymal stem cells treatment predict a significant improvement versus 7,12-dimethyl benz [a] anthracene group through the modulation of growth factors that confront bone marrow dysplasia. In the same direction treatment of 7,12-dimethyl benz [a] anthracene group with mesenchymal stem cells, it induced apoptosis and increased the homing efficacy to bone marrow. In conclusion, mesenchymal stem cells improve hematopoiesis and alleviate inflammation, and modulated PI3K/AKT signaling pathway contributed to experimental leukemogenesis.

Yang MH, Lee JH, Ko JH, et al.
Brassinin Represses Invasive Potential of Lung Carcinoma Cells through Deactivation of PI3K/Akt/mTOR Signaling Cascade.
Molecules. 2019; 24(8) [PubMed] Article available free on PMC after 01/07/2020 Related Publications
The epithelial-mesenchymal transition (EMT) is a phenomenon that facilitates epithelial cells to acquire invasive potential to induce the initiation the metastatic spread of tumor cells. Here, we determined if brassinin (BSN) can affect the EMT process and deciphered its anti-cancer effects. BSN attenuated the levels of EMT linked genes and suppressed transforming growth factor beta (TGF-β)-mediated regulation of diverse mesenchymal markers. Additionally, BSN did increase the expression of various epithelial marker proteins in lung cancer cells. TGF-β-induced morphological changes and induction of invasive ability of tumor cells was also found to be abrogated by BSN treatment. Finally, BSN not only suppressed constitutive, but also inducible phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) phosphorylation in tumor cells.

Forés-Martos J, Catalá-López F, Sánchez-Valle J, et al.
Transcriptomic metaanalyses of autistic brains reveals shared gene expression and biological pathway abnormalities with cancer.
Mol Autism. 2019; 10:17 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
Background: Epidemiological and clinical evidence points to cancer as a comorbidity in people with autism spectrum disorders (ASD). A significant overlap of genes and biological processes between both diseases has also been reported.
Methods: Here, for the first time, we compared the gene expression profiles of ASD frontal cortex tissues and 22 cancer types obtained by differential expression meta-analysis and report gene, pathway, and drug set-based overlaps between them.
Results: Four cancer types (brain, thyroid, kidney, and pancreatic cancers) presented a significant overlap in gene expression deregulations in the same direction as ASD whereas two cancer types (lung and prostate cancers) showed differential expression profiles significantly deregulated in the opposite direction from ASD. Functional enrichment and LINCS L1000 based drug set enrichment analyses revealed the implication of several biological processes and pathways that were affected jointly in both diseases, including impairments of the immune system, and impairments in oxidative phosphorylation and ATP synthesis among others. Our data also suggest that brain and kidney cancer have patterns of transcriptomic dysregulation in the PI3K/AKT/MTOR axis that are similar to those found in ASD.
Conclusions: Comparisons of ASD and cancer differential gene expression meta-analysis results suggest that brain, kidney, thyroid, and pancreatic cancers are candidates for direct comorbid associations with ASD. On the other hand, lung and prostate cancers are candidates for inverse comorbid associations with ASD. Joint perturbations in a set of specific biological processes underlie these associations which include several pathways previously implicated in both cancer and ASD encompassing immune system alterations, impairments of energy metabolism, cell cycle, and signaling through PI3K and G protein-coupled receptors among others. These findings could help to explain epidemiological observations pointing towards direct and inverse comorbid associations between ASD and specific cancer types and depict a complex scenario regarding the molecular patterns of association between ASD and cancer.

Rui QH, Ma JB, Liao YF, et al.
Effect of lncRNA HULC knockdown on rat secreting pituitary adenoma GH3 cells.
Braz J Med Biol Res. 2019; 52(4):e7728 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
Pituitary adenoma is one of the most common tumors in the neuroendocrine system. This study investigated the effects of long non-coding RNAs (lncRNAs) highly up-regulated in liver cancer (HULC) on rat secreting pituitary adenoma GH3 cell viability, migration, invasion, apoptosis, and hormone secretion, as well as the underlying potential mechanisms. Cell transfection and qRT-PCR were used to change and measure the expression levels of HULC, miR-130b, and FOXM1. Cell viability, migration, invasion, and apoptosis were assessed using trypan blue staining assay, MTT assay, two-chamber transwell assay, Guava Nexin assay, and western blotting. The concentrations of prolactin (PRL) and growth hormone (GH) in culture supernatant of GH3 cells were assessed using ELISA. The targeting relationship between miR-130b and FOXM1 was verified using dual luciferase activity. Finally, the expression levels of key factors involved in PI3K/AKT/mTOR and JAK1/STAT3 pathways were evaluated using western blotting. We found that HULC was highly expressed in GH3 cells. Overexpression of HULC promoted GH3 cell viability, migration, invasion, PRL and GH secretion, as well as activated PI3K/AKT/mTOR and JAK1/STAT3 pathways. Knockdown of HULC had opposite effects and induced cell apoptosis. HULC negatively regulated the expression of miR-130b, and miR-130b participated in the effects of HULC on GH3 cells. FOXM1 was a target gene of miR-130b, which was involved in the regulation of GH3 cell viability, migration, invasion, and apoptosis, as well as PI3K/AKT/mTOR and JAK1/STAT3 pathways. In conclusion, HULC tumor-promoting roles in secreting pituitary adenoma might be via down-regulating miR-130b, up-regulating FOXM1, and activating PI3K/AKT/mTOR and JAK1/STAT3 pathways.

Zhu H, Gan X, Jiang X, et al.
ALKBH5 inhibited autophagy of epithelial ovarian cancer through miR-7 and BCL-2.
J Exp Clin Cancer Res. 2019; 38(1):163 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
BACKGROUND: ALKBH5 regulated the malignant behavior of breast cancer and glioblastoma. However, the expression and function of ALKBH5 in epithelial ovarian cancer have not yet been determined. In the present study, we investigated the expression and function of ALKBH5 in epithelial ovarian cancer with respect to its potential role in the tumorigenesis of the disease as well as an early diagnostic marker.
METHODS: Immunohistochemistry and western blot were used to detect protein expression. Gene silencing and over-expression experiment were used to study gene function. Cell proliferation assay and Matrigel invasion assays were used to detect cell proliferation and invasion, respectively. The nude mouse tumor formation experiment was used to evaluate the growth of cells in vivo.
RESULTS: The expression of ALKBH5 was found to be increased in epithelial ovarian cancer tissue as compared to the normal ovarian tissues. The silencing of ALKBH5 in SKOV3 cells enhanced the autophagy and inhibited the proliferation and invasion in vitro and in vivo, whereas the ectopic expression of ALKBH5 in A2780 cells exerted an opposite effect. Mechanical study revealed that ALKBH5 physically interacted with HuR. ALKBH5 activated EGFR-PIK3CA-AKT-mTOR signaling pathway. Also, ALKBH5 enhanced the stability of BCL-2 mRNA and promoted the interaction between Bcl-2 and Beclin1.
CONCLUSION: Overall, the present study identified ALKBH5 as a candidate oncogene in epithelial ovarian cancer and a potential target for ovarian cancer therapy.

Mele L, la Noce M, Paino F, et al.
Glucose-6-phosphate dehydrogenase blockade potentiates tyrosine kinase inhibitor effect on breast cancer cells through autophagy perturbation.
J Exp Clin Cancer Res. 2019; 38(1):160 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
BACKGROUND: Glucose-6-phospate dehydrogenase (G6PD) is the limiting enzyme of the pentose phosphate pathway (PPP) correlated to cancer progression and drug resistance. We previously showed that G6PD inhibition leads to Endoplasmic Reticulum (ER) stress often associated to autophagy deregulation. The latter can be induced by target-based agents such as Lapatinib, an anti-HER2 tyrosine kinase inhibitor (TKI) largely used in breast cancer treatment.
METHODS: Here we investigate whether G6PD inhibition causes autophagy alteration, which can potentiate Lapatinib effect on cancer cells. Immunofluorescence and flow cytometry for LC3B and lysosomes tracker were used to study autophagy in cells treated with lapatinib and/or G6PD inhibitors (polydatin). Immunoblots for LC3B and p62 were performed to confirm autophagy flux analyses together with puncta and colocalization studies. We generated a cell line overexpressing G6PD and performed synergism studies on cell growth inhibition induced by Lapatinib and Polydatin using the median effect by Chou-Talay. Synergism studies were additionally validated with apoptosis analysis by annexin V/PI staining in the presence or absence of autophagy blockers.
RESULTS: We found that the inhibition of G6PD induced endoplasmic reticulum stress, which was responsible for the deregulation of autophagy flux. Indeed, G6PD blockade caused a consistent increase of autophagosomes formation independently from mTOR status. Cells engineered to overexpress G6PD became resilient to autophagy and resistant to lapatinib. On the other hand, G6PD inhibition synergistically increased lapatinib-induced cytotoxic effect on cancer cells, while autophagy blockade abolished this effect. Finally, in silico studies showed a significant correlation between G6PD expression and tumour relapse/resistance in patients.
CONCLUSIONS: These results point out that autophagy and PPP are crucial players in TKI resistance, and highlight a peculiar vulnerability of breast cancer cells, where impairment of metabolic pathways and autophagy could be used to reinforce TKI efficacy in cancer treatment.

Chen MK, Peng CC, Maner RS, et al.
Geniposide ameliorated fluoxetine-suppressed neurite outgrowth in Neuro2a neuroblastoma cells.
Life Sci. 2019; 226:1-11 [PubMed] Related Publications
AIM: Fluoxetine (FXT), a selective serotonin reuptake inhibitor (SSRI), is one of the most common psychiatric medications clinically prescribed; while over-produced serotonin may suppress neurite development. The role of major iridoids like geniposide (GPS) and genipin (GNP) from Gardenia jasminoides Ellis fruit (family Rubiaceae) in ameliorating the anti-neurite outgrowth effect of FXT is poorly understood. In this study, the effects of these iridoids on FXT-suppressed neurite outgrowth in Neuro2a neuroblastoma cells were investigated.
MAIN METHODS: Neuro2a cells were treated with FXT and GPS. The effect of GPS-FXT co-treatment on neurite outgrowth was observed using inverted phase-contrast microscope imaging system, while neurite outgrowth markers - microtubule-associated protein-2 (MAP2) and growth-associated protein 43 (GAP43) were analyzed using RT-PCR, Western blot and immunofluorescence staining. The transcription factor-cAMP response element binding (CREB), and signaling pathways - mitogen-activated protein kinase (MAPK) and protein kinase B/mammalian target of rapamycin (AKT/mTOR) were also analyzed with the help of Western blot.
KEY FINDINGS: The results showed that FXT decreased the neurite outgrowth in Neuro2a cells and also downregulated gene and protein expression of MAP2 and GAP43. It also downregulated the protein expression of phosphorylated-CREB, MAPK, and AKT/mTOR signaling pathways. In contrast, GPS counteracted the effects of FXT. GPS-FXT co-treatment increased the percentage of neurite-bearing cells by 3.6-fold at 200 μM as compared to FXT treatment only.
SIGNIFICANCE: This study has provided the possible molecular mechanism showing how FXT exerted its detrimental side-effects on the neurite differentiation, and via the same mechanism how GPS attenuated these side effects.

Wang Y, Hou Y, Zhang W, et al.
Lipolytic inhibitor G0S2 modulates glioma stem-like cell radiation response.
J Exp Clin Cancer Res. 2019; 38(1):147 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
BACKGROUND: Ionizing radiation (IR) therapy is the standard first-line treatment for newly diagnosed patients with glioblastoma (GBM), the most common and malignant primary brain tumor. However, the effects of IR are limited due to the aberrant radioresistance of GBM.
METHODS: Transcriptome analysis was performed using RNA-seq in radioresistant patient-derived glioma stem-like cells (GSCs). Survival of glioma patient and mice bearing-brain tumors was analyzed by Kaplan-Meier survival analysis. Lipid droplet and γ-H2AX foci-positive cells were evaluated using immunofluorescence staining.
RESULTS: Lipolytic inhibitor G0/G1 switch gene 2 (G0S2) is upregulated in radioresistant GSCs and elevated in clinical GBM. GBM patients with high G0S2 expression had significantly shorter overall survival compared with those with low expression of G0S2. Using genetic approaches targeting G0S2 in glioma cells and GSCs, we found that knockdown of G0S2 promoted lipid droplet turnover, inhibited GSC radioresistance, and extended survival of xenograft tumor mice with or without IR. In contrast, overexpression of G0S2 promoted glioma cell radiation resistance. Mechanistically, high expression of G0S2 reduced lipid droplet turnover and thereby attenuated E3 ligase RNF168-mediated 53BP1 ubiquitination through activated the mechanistic target of rapamycin (mTOR)-ribosomal S6 kinase (S6K) signaling and increased 53BP1 protein stability in response to IR, leading to enhanced DNA repair and glioma radioresistance.
CONCLUSIONS: Our findings uncover a new function for lipolytic inhibitor G0S2 as an important regulator for GSC radioresistance, suggesting G0S2 as a potential therapeutic target for treating gliomas.

Saccà CD, Gorini F, Ambrosio S, et al.
Inhibition of lysine-specific demethylase LSD1 induces senescence in Glioblastoma cells through a HIF-1α-dependent pathway.
Biochim Biophys Acta Gene Regul Mech. 2019; 1862(5):535-546 [PubMed] Related Publications
Senescence is a stress-responsive cellular program that leads to cell cycle arrest. In cancer cells, senescence has profound implications for tumor aggressiveness and clinical outcome, but the molecular events that provoke cancer cells to undergo senescence remain unclear. Herein, we provide evidence that the histone demethylase LSD1/KDM1A supports the growth of Glioblastoma tumor cells and its inhibition triggers senescence response. LSD1 is a histone modifier that participates in key aspects of gene transcription as well as in the regulation of methylation dynamics of non-histone proteins. We found that down-regulation of LSD1 inhibits Glioblastoma cell growth, impairs mTOR pathway and cell migration and induces senescence. At mechanistic level, we found that LSD1 regulates HIF-1α protein stability. Pharmacological inhibition or siRNA-mediated silencing of LSD1 expression effectively reduces HIF-1α protein levels, which suffices for the induction of senescence. Our findings elucidate a mechanism whereby LSD1 controls senescence in Glioblastoma tumor cells through the regulation of HIF-1α, and we propose the novel defined LSD1/HIF-1α axis as a new target for the therapy of Glioblastoma tumors.

Yang L, Peng X, Li Y, et al.
Long non-coding RNA HOTAIR promotes exosome secretion by regulating RAB35 and SNAP23 in hepatocellular carcinoma.
Mol Cancer. 2019; 18(1):78 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
BACKGROUND: Emerging evidence indicates that tumor cells release a large amount of exosomes loaded with cargos during tumorigenesis. Exosome secretion is a multi-step process regulated by certain related molecules. Long non-coding RNAs (lncRNAs) play an important role in hepatocellular carcinoma (HCC) progression. However, the role of lncRNA HOTAIR in regulating exosome secretion in HCC cells remains unclear.
METHODS: We analyzed the relationship between HOTAIR expression and exosome secretion-related genes using gene set enrichment analysis (GSEA). Nanoparticle tracking analysis was performed to validate the effect of HOTAIR on exosome secretion. The transport of multivesicular bodies (MVBs) after overexpression of HOTAIR was detected by transmission electron microscopy and confocal microscopy analysis of cluster determinant 63 (CD63) with synaptosome associated protein 23 (SNAP23). The mechanism of HOTAIR's regulation of Ras-related protein Rab-35 (RAB35), vesicle associated membrane protein 3 (VAMP3), and SNAP23 was assessed using confocal co-localization analysis, phosphorylation assays, and rescue experiments.
RESULTS: We found an enrichment of exosome secretion-related genes in the HOTAIR high expression group. HOTAIR promoted the release of exosomes by inducing MVB transport to the plasma membrane. HOTAIR regulated RAB35 expression and localization, which controlled the docking process. Moreover, HOTAIR facilitated the final step of fusion by influencing VAMP3 and SNAP23 colocalization. In addition, we validated that HOTAIR induced the phosphorylation of SNAP23 via mammalian target of rapamycin (mTOR) signaling.
CONCLUSION: Our study demonstrated a novel function of lncRNA HOTAIR in promoting exosome secretion from HCC cells and provided a new understanding of lncRNAs in tumor cell biology.

Djuzenova CS, Fiedler V, Memmel S, et al.
Differential effects of the Akt inhibitor MK-2206 on migration and radiation sensitivity of glioblastoma cells.
BMC Cancer. 2019; 19(1):299 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
BACKGROUND: Most tumor cells show aberrantly activated Akt which leads to increased cell survival and resistance to cancer radiotherapy. Therefore, targeting Akt can be a promising strategy for radiosensitization. Here, we explore the impact of the Akt inhibitor MK-2206 alone and in combination with the dual PI3K and mTOR inhibitor PI-103 on the radiation sensitivity of glioblastoma cells. In addition, we examine migration of drug-treated cells.
METHODS: Using single-cell tracking and wound healing migration tests, colony-forming assay, Western blotting, flow cytometry and electrorotation we examined the effects of MK-2206 and PI-103 and/or irradiation on the migration, radiation sensitivity, expression of several marker proteins, DNA damage, cell cycle progression and the plasma membrane properties in two glioblastoma (DK-MG and SNB19) cell lines, previously shown to differ markedly in their migratory behavior and response to PI3K/mTOR inhibition.
RESULTS: We found that MK-2206 strongly reduces the migration of DK-MG but only moderately reduces the migration of SNB19 cells. Surprisingly, MK-2206 did not cause radiosensitization, but even increased colony-forming ability after irradiation. Moreover, MK-2206 did not enhance the radiosensitizing effect of PI-103. The results appear to contradict the strong depletion of p-Akt in MK-2206-treated cells. Possible reasons for the radioresistance of MK-2206-treated cells could be unaltered or in case of SNB19 cells even increased levels of p-mTOR and p-S6, as compared to the reduced expression of these proteins in PI-103-treated samples. We also found that MK-2206 did not enhance IR-induced DNA damage, neither did it cause cell cycle distortion, nor apoptosis nor excessive autophagy.
CONCLUSIONS: Our study provides proof that MK-2206 can effectively inhibit the expression of Akt in two glioblastoma cell lines. However, due to an aberrant activation of mTOR in response to Akt inhibition in PTEN mutated cells, the therapeutic window needs to be carefully defined, or a combination of Akt and mTOR inhibitors should be considered.

Gao XF, He HQ, Zhu XB, et al.
LncRNA SNHG20 promotes tumorigenesis and cancer stemness in glioblastoma via activating PI3K/Akt/mTOR signaling pathway.
Neoplasma. 2019; 2019:532-542 [PubMed] Related Publications
Long noncoding RNAs (lncRNAs) play crucial roles in the development of human cancers. LncRNA small nucleolar RNA host gene 20 (SNHG20) has been reported to be an oncogene in several cancers, whereas the specific role of SNHG20 in glioblastoma is unclear. In this study, we found that SNHG20 was significantly upregulated in glioblastoma tissues and cell lines. Survival analysis suggested that high expression of SNHG20 indicated the low overall survival rate of glioblastoma patients. Subsequently, gain or loss-of-function assays were carried out to examine the effect of SNHG20 on glioblastoma cell proliferation and apoptosis. We found that SNHG20 knockdown obviously suppressed cell proliferation, increased cell apoptosis and impaired stem properties, while SNHG20 overexpression led to the opposite results. In vivo experiment demonstrated that knockdown of SNHG20 efficiently suppressed cell growth in vivo. Furthermore, western blotting demonstrated that the PI3K/Akt/mTOR signaling pathway was activated by SNHG20 in glioblastoma cells. At last, rescue assays validated that PI3K/Akt/mTOR signaling pathway involved in the glioblastoma progression mediated by SNHG20. Taken together, this study revealed that SNHG20 regulated PI3K/Akt/mTOR signaling pathway to promote tumorigenesis and stemness of glioblastoma.

Zou Y, Chen M, Zhang S, et al.
TRPC5‑induced autophagy promotes the TMZ‑resistance of glioma cells via the CAMMKβ/AMPKα/mTOR pathway.
Oncol Rep. 2019; 41(6):3413-3423 [PubMed] Related Publications
Temozolomide (TMZ) is the first choice chemotherapy agent against glioblastoma, but the TMZ chemotherapy resistance has restricted the clinical application. Although autophagy is considered an adaptive response for cell survival under the pressure of chemotherapy and associated with chemotherapy resistance, its initiator and the precise molecular mechanism remains unknown. In the present study, it was determined that TMZ increases the transient receptor potential cation channel subfamily C member 5 (TRPC5) protein expression and the basal autophagy level, and the upregulation of autophagy is mediated by TRPC5 in glioma cells. Additionally, knockdown of TRPC5 upregulated the chemotherapy sensitivity in vitro and in vivo. Furthermore, TRPC5‑small interfering RNA and pharmacological inhibition indicated that the Ca2+/calmodulin dependent protein kinase β (CaMKKβ)/AMP‑activated protein kinase α (AMPKα)/mechanistic target of rapamycin kinase (mTOR) pathway mediates cell survival autophagy during TMZ treatment. In addition, TMZ‑resistant U87/TMZ cells retained a high basal autophagy level, while silence of TRPC5 expression or inhibition of autophagy reversed TMZ resistance. Thus, the present study revealed that TRPC5, an initiator of autophagy, upregulated TMZ resistance via the CaMKKβ/AMPKα/mTOR pathway and this indicated a novel therapeutic site for drug resistance in glioma chemotherapy.

Lin JF, Tsai TF, Lin YC, et al.
Benzyl isothiocyanate suppresses IGF1R, FGFR3 and mTOR expression by upregulation of miR-99a-5p in human bladder cancer cells.
Int J Oncol. 2019; 54(6):2106-2116 [PubMed] Related Publications
Benzyl isothiocyanate (BITC) is known for its pharmacological properties against malignant neoplasm, including bladder cancer (BC). The current study investigated microRNAs (miRNA or miR) expression profiles with an emphasis on the role of miR‑99a‑5p in BITC‑treated BC cells. A quantitative polymerase chain reaction (qPCR) microarray containing 79 aberrantly expressed miRNAs in BC was used to detect miRNA expression in BITC‑treated cells. Several dysregulated miRNAs were identified and further confirmed using miRNA stem‑loop reverse transcription (RT)‑qPCR in 5637 cells. Insulin‑like growth factor 1 receptor (IGF1R), fibroblast growth factor receptor 3 (FGFR3) and mammalian target of rapamycin (mTOR) expression were determined by RT‑qPCR and western blotting. Cell viability was evaluated using WST‑1 reagent and apoptosis was monitored by determining the levels of cleaved‑poly ADP‑ribose polymerase and cleaved‑caspase‑3. BITC treatment significantly upregulated miR‑99a‑5p levels in a dose‑dependent manner. miR‑99a‑5p overexpression decreased IGF1R, mTOR and FGFR3 expression, predicted targets of miR‑99a‑5p. In addition, antisense miR‑99a‑5p sequences inhibited BITC‑induced miR‑99a‑5p overexpression, resulting in the restoration of protein expression and decreased cell viability. The current study identified multiple miRNAs responsive to BITC treatment, including miR‑99a‑5p. In addition, the induction of miR‑99a‑5p decreased IGF1R, mTOR and FGFR3 expression in BITC‑treated BC cells. The current study provided novel insight into the antitumor mechanism by which BITC restores miR‑99a‑5p expression and decreases cancer cell survival.

Zhang J, Li J, Li S, et al.
miR‑802 inhibits the aggressive behaviors of non‑small cell lung cancer cells by directly targeting FGFR1.
Int J Oncol. 2019; 54(6):2211-2221 [PubMed] Related Publications
Emerging reports have revealed that several microRNAs (miRNAs) are abnormally expressed in non‑small cell lung cancer (NSCLC). miRNAs have been identified as oncogenes or tumor suppressors, and regulate various biological processes including oncogenesis and development. miR‑802 is dysregulated in multiple types of human cancer, and exerts tumor‑suppressive or promoting roles. However, the expression levels and functional roles of miR‑802 in NSCLC remain largely unknown. In the present study, miR‑802 expression was demonstrated to be decreased in NSCLC tissues and cell lines. A low miR‑802 expression was significantly correlated with the tumor stage, lymph node metastasis and brain metastasis in NSCLC patients. Restoring miR‑802 expression inhibited NSCLC cell proliferation and colony formation, induced cell apoptosis, decreased cell migration and invasion in vitro, and hindered in vivo tumor growth. Mechanistically, fibroblast growth factor receptor 1 (FGFR1) was confirmed as the target gene of miR‑802 in NSCLC cells. In addition, FGFR1 silencing mimicked the tumor‑suppressing roles of miR‑802 upregulation in NSCLC cells. Furthermore, rescue experiments revealed that FGFR1 reintroduction rescued the miR‑802‑induced inhibition of the malignant phenotypes in NSCLC cells. Notably, miR‑802 was able to deactivate the phosphoinositide 3‑kinase (PI3K)/AKT serine/threonine kinase (Akt)/mammalian target of rapamycin (mTOR) pathway in NSCLC cells in vitro and in vivo. Overall, these results demonstrated that miR‑802 could downregulate FGFR1 expression, thereby deactivating the PI3K/Akt/mTOR pathway and inhibiting the malignant development of NSCLC. Thus, miR‑802 may be a therapeutic candidate for patients with NSCLC.

Zhang Y, Zhao Z, Li S, et al.
Inhibition of miR‑214 attenuates the migration and invasion of triple‑negative breast cancer cells.
Mol Med Rep. 2019; 19(5):4035-4042 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
Triple‑negative breast cancer (TNBC) is a subtype of breast cancer. MicroRNA (miR)‑214 is closely associated with controlling the development of tumor cells; therefore, in the present study, the target gene and effects of miR‑214 on TNBC cells were explored. Luciferase activity was examined by luciferase reporter assay. The viability, invasion and migration of MDA‑MB‑231 TNBC cells were measured using Cell Counting kit‑8, Transwell and wound‑healing assays, respectively. The expression levels of various factors were determined using reverse transcription‑quantitative polymerase chain reaction and western blotting. The results demonstrated that the expression levels of miR‑214 were higher and the levels of α1‑antitrypsin (α1‑AT) were lower in TNBC tissues compared with in normal tissues. Subsequently, α1‑AT was revealed to be a target of miR‑214. Furthermore, inhibition of miR‑214 decreased cell viability, invasion and migration, enhanced the expression of E‑cadherin and tissue inhibitor of metalloproteinases‑2, and reduced the expression of metastatic tumour antigen 1 and matrix metalloproteinase‑2. Inhibition of miR‑214 also significantly downregulated the phosphorylation of protein kinase B (Akt) and mammalian target of rapamycin (mTOR), and markedly downregulated that of phosphoinositide 3‑kinase (PI3K); however, the expression levels of total PI3K, Akt and mTOR remained stable in all groups. Taken together, these findings indicated that α1‑AT may be a target of miR‑214. Downregulation of miR‑214 markedly suppressed the viability, migration and invasion of MDA‑MB‑231 cells, and inhibited the PI3K/Akt/mTOR pathway. These findings suggested that miR‑214 targeting α1‑AT may be a potential mechanism underlying TNBC development.

Yang X, Guo F, Peng Q, et al.
Suppression of in vitro and in vivo human ovarian cancer growth by isoacteoside is mediated via sub-G1 cell cycle arrest, ROS generation, and modulation of AKT/PI3K/m-TOR signalling pathway.
J BUON. 2019 Jan-Feb; 24(1):285-290 [PubMed] Related Publications
PURPOSE: The purpose of the present study was to investigate the anticancer properties of isoacteoside against OVCAR-3 human ovarian cancer cells. Its effects on apoptosis, reactive oxygen species (ROS) generation, cell invasion, cell cycle arrest and its effects on tumor volume and weight were also evaluated in the current study.
METHODS: MTT assay was used to study the cytotoxic effects of the compound on the cell viability. Effects on apoptosis and cell cycle arrest were evaluated by flow cytometry. In vitro wound healing assay and matrigel assay were carried out to study the effects of isoacteoside on cell migration and cell invasion respectively. Non-cancer ovarian cell line SV-40 served as control.
RESULTS: Isoacteoside exerted both dose-dependent as well as time-dependent growth inhibitory effects on ovarian cancer cells with IC50 values of 15 µM at 24h incubation. Isoacteoside led to early and late apoptosis induction in these cells. Isoacteoside also led to sub-G1 cell cycle arrest which showed strong dose-dependence. Isoacteoside treatment also led to inhibition of cell migration and cell invasion. The results revealed that OVCAR-3 tumor growth was significantly suppressed by isoacteoside administration, compared with that in the control group. At the end of the 5-week period of isoacteoside treatment, the average tumor growth and volume in the untreated control group were considerably higher than those in the treated groups.
CONCLUSION: In brief, the current study indicates that isoacteoside has a great potential in suppressing both in vitro and in vivo ovarian cancer cell growth and can be used as a possible anticancer agent.

Cui C, Li S, Wu D
Znhit1 inhibits breast cancer by up-regulating PTEN to deactivate the PI3K/Akt/mTOR pathway.
Life Sci. 2019; 224:204-211 [PubMed] Related Publications
AIMS: Breast cancer (BC) is the most frequently diagnosed cancer, ranking sixth as the cause of death among females in China. Zinc finger HIT-type containing 1 (Znhit1) is a pivotal factor for inhibition of gene mutation and cell proliferation. Due to the unknown function of Znhit1 in cancers, we aimed to explore the role of Znhit1 in BC as well as the underlying mechanisms.
MAIN METHODS: Znhit1 expression in clinical specimens and cell lines of BC was measured by quantitative reverse transcription PCR and Western blot analysis. Then, the effects of Znhit1 overexpression on cell proliferation, apoptosis and invasion of BC cells as well as in vivo tumor growth were assessed. The interactions among Znhit1, PTEN and the downstream PI3K/Akt/mTOR pathway were evaluated by Western blot analysis. Finally, the role of Znhit1 in prognosis was analyzed in clinical specimens.
KEY FINDINGS: Znhit1 was down-regulated in BC cell lines and clinical specimens. Znhit1 overexpression induced apoptosis and repressed proliferation and invasion of BC cells. Moreover, Znhit1 overexpression induced cell cycle arrest at G0/G1 stage. In vivo data showed that Znhit1 overexpression inhibited BC tumor growth in mice. Further experiments showed Znhit1 affected BC through up-regulating PTEN, along with inactivation of the PI3K/Akt/mTOR pathway. We finally proved that high expression of Znhit1 indicated improved prognosis.
SIGNIFICANCE: Znhit1 overexpression inhibited BC tumorigenesis possibly through PTEN-mediated inactivation of the PI3K/Akt/mTOR pathway. Additionally, high expression of Znhit1 indicated improved prognosis.

Vahabi M, Pulito C, Sacconi A, et al.
miR-96-5p targets PTEN expression affecting radio-chemosensitivity of HNSCC cells.
J Exp Clin Cancer Res. 2019; 38(1):141 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cancer worldwide. They are typically characterized by a high incidence of local recurrence, which is the most common cause of death in HNSCC patients. TP53 is the most frequently mutated gene in HNSCC and patients carrying TP53 mutations are associated with a higher probability to develop local recurrence. MiRNAs, which are among the mediators of the oncogenic activity of mt-p53 protein, emerge as an appealing tool for screening, diagnosis and prognosis of cancer. We previously identified a signature of 12 miRNAs whose aberrant expression associated with TP53 mutations and was prognostic for HNSCC. Among them miR-96-5p emerges as an oncogenic miRNAs with prognostic significance in HNSCC.
METHODS: To evaluate the oncogenic role of miR-96-5p in a tumoral context, we performed colony formation, cell migration and cell viability assays in two HNSCC cell lines transfected for miR-96-5p mimic or inhibitor and treated with or without radio/chemo-therapy. In addition, to identify genes positively and negatively correlated to miR-96-5p expression in HNSCC, we analyzed the correlation between gene expression and miR-96-5p level in the subset of TCGA HNSCC tumors carrying missense TP53 mutations by Spearman and Pearson correlation. To finally identify targets of miR-96-5p, we used in silico analysis and the luciferase reporter assay to confirm PTEN as direct target.
RESULTS: Our data showed that overexpression of miR-96-5p led to increased cell migration and radio-resistance, chemotherapy resistance in HNSCC cells. In agreement with these results, among the most statistically significant pathways in which miR-96-5p is involved, are focal Adhesion, extracellular matrix organization and PI3K-Akt-mTOR-signaling pathway. As a direct target of miR-96-5p, we identified PTEN, the main negative regulator of PI3K-Akt signalling pathway activation.
CONCLUSIONS: These results highlight a new mechanism of chemo/radio-resistance insurgence in HNSCC cells and support the possibility that miR-96-5p expression could be used as a novel promising biomarker to predict radiotherapy response and local recurrence development in HNSCC patients. In addition, the identification of pathways in which miR-96-5p is involved could contribute to develop new therapeutic strategies to overcome radio-resistance.

Luo C, Cen S, Ding G, Wu W
Mucinous colorectal adenocarcinoma: clinical pathology and treatment options.
Cancer Commun (Lond). 2019; 39(1):13 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
Mucinous colorectal adenocarcinoma is a distinct subtype of colorectal cancer (CRC) characterized by the presence of abundant extracellular mucin which accounts for at least 50% of the tumor volume. Mucinous colorectal adenocarcinoma is found in 10%-20% of CRC patients and occurs more commonly in female and younger patients. Moreover, mucinous colorectal adenocarcinoma is more frequently located in the proximal colon and diagnosed at an advanced stage. Based on its molecular context, mucinous colorectal adenocarcinoma is associated with the overexpression of mucin 2 (MUC2) and mucin 5AC (MUC5AC) proteins. At the same time, it shows higher mutation rates in the fundamental genes of the RAS/MAPK and PI3K/Akt/mTOR pathways. Mucinous colorectal adenocarcinoma also shows higher rates of microsatellite instability (MSI) than non-mucinous colorectal adenocarcinoma which might correlate it with Lynch syndrome and the CpG island methylator phenotype. The prognosis of mucinous colorectal adenocarcinoma as to non-mucinous colorectal adenocarcinoma is debatable. Further, the impaired responses of mucinous colorectal adenocarcinoma to palliative or adjuvant chemotherapy warrant more studies to be performed for a specialized treatment for these patients. In this review, we discuss the molecular background and histopathology of mucinous colorectal adenocarcinoma, and provide an update on its prognosis and therapeutics from recent literatures.

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