Decreased Nuclear Immunoexpression of ING3 is a Frequent Event in Lip Carcinogenesis.

PURPOSE: Evaluate the immunohistochemical expression of the ING3 in actinic cheilitis and squamous cell carcinoma of the lower lip. METHODS: Forty-five specimens of actinic cheilitis and 48 specimens of squamous cell carcinoma of the lower lip were submitted to immunohistochemical detection of ING3. The protein expression in different cellular sublocations was compared between the two groups, and associations with the clinicopathological variables were analyzed. A significance level of 5% was adopted for all tests. RESULTS: Deaths were significantly more frequent in tumors with a high histopathological risk score (p < 0.05). In actinic cheilitis, significant differences were found in the nucleus-cytoplasmic expression of ING3 and expression restricted to the cytoplasm with binary histopathological grading (p < 0.05). In squamous cell carcinoma of the lower lip, there was no statistically significant difference when comparing ING3 expressions with clinical and morphological parameters (p > 0.05). Nucleo-cytoplasmic ING3 expression was significantly lower in squamous cell carcinoma of the lower lip when compared to actinic cheilitis (p < 0.05) and the expression restricted to the cytoplasm was significantly higher in squamous cell carcinoma of the lower lip (p < 0.05). CONCLUSION: The results of this study suggest that there is a marked decrease in the nuclear expression of ING3 as malignant progression occurs, indicating an impaired tumor suppressor function of this protein in actinic cheilitis and squamous cell carcinoma of the lower lip.

[Characteristics of gastric neuroendocrine tumors and the PDX-1 transcription factor expression]. / Kharakteristika neiroendokrinnykh opukholei zheludka i ekspressiya v nikh transkriptsionnogo faktora PDX-1.

OBJECTIVE: To study the features of gastric neuroendocrine tumors (NETs) and the diagnostic and prognostic significance of PDX-1 expression in them. MATERIAL AND METHODS: 207 NETs identified in 56 men and 115 women (59 had multiple NETs), and 94 cases of gastric cancer (comparison group) were studied morphologically and immunohistochemically. RESULTS: In more than half of the cases (54.93%), NETs were localized in the body of the stomach; the cardiac and antral parts of the stomach accounted for 8.64% and 11.73%, respectively. NETs of the cardiac region predominated in men, and of the body and antrum - in women. NETs of the cardiac region predominated in men, and of the body and antrum - in women. The vast majority of NETs were highly differentiated (89.20%), of which Grade 1, 2 and 3 were 55.41%, 40.76% and 3.82%, respectively. Neuroendocrine carcinomas (NEC) accounted for 10.80% of all NET cases. NECs were more often localized in the cardiac part of the stomach and accounted for 35.71% of all NETs in the cardiac part. The share of NEC among all NETs of the antrum was 15.79%, of the body of the stomach - only 3.37%. Metastases were found in 17.90% of NETs. Expression of PDX-1 was detected in 44.73% of NETs, 70% of NECs and 74.50% of gastric cancers. CONCLUSION: PDX-1 is involved in the mechanisms of precancerous and cancerous lesions of the stomach and its overexpression is detected in the majority of the most malignant NETs and gastric cancers.

Expression profile and prognostic significance of HOXB13 in rectal cancer.

BACKGROUND: This study aimed to investigate the expression pattern and prognostic significance of HOXB13 in rectal cancer. METHODS: HOXB13 expression in rectal cancer and normal adjacent tissues was detected by reverse transcriptase-polymerase chain reaction and immunohistochemistry, and its clinicopathological characteristics and prognosis were statistically tested. Furthermore, we evaluated the association between tumor immune infiltrating cells and HOXB13 using the tumor immune estimation resource (TIMER) database. The potential biological mechanism associated with HOXB13 overexpression was investigated by gene set enrichment analysis (GSEA). RESULTS: The expression of HOXB13 messenger RNA and protein in human rectal cancer tissues were significantly higher than those in the normal adjacent tissues (P < 0.05). HOXB13 expression was significantly correlated with depth of invasion, lymphatic invasion, lymph node metastasis, distant metastasis, and pathological tumor node metastasis stage (P < 0.05). Kaplan-Meier survival curves confirmed that HOXB13 overexpression was correlated negatively with overall survival and disease-free survival in rectal cancer (P < 0.05). Also, multivariate Cox regression analysis demonstrated that HOXB13 expression, age, and lymphatic invasion were independent prognostic factors in rectal cancer (P < 0.05). Plus, the results from the TIMER database indicated that HOXB13 expression has a significant association with several immune cell infiltrates. Finally, the GSEA results indicated that HOXB13 participated in the various immune-associated processes, including natural killer cell-mediated cytotoxicity and the T-cell receptor signaling pathway. CONCLUSION: Our study showed an essential role of HOXB13 in rectal cancer immunity and prognosis. Significantly, the overexpression of HOXB13 leads to the worse prognosis for patients with rectal cancer, which will contribute to understanding molecular mechanisms associated with tumor pathogenesis and prognosis in this disease.

MiR-369-5p inhibits the proliferation and migration of hepatocellular carcinoma cells by down-regulating HOXA13 expression.

MicroRNA (miRNA) is vital to the progression of hepatocellular carcinoma (HCC). Thereinto, miR-369-5p could yield assorted effects on various cancers, but there are few reports concerning the effect of miR-369-5p on HCC. Thus this study aimed to investigate the effect and mechanism of miR-369-5p in HCC. The data of miR-369-5p and HOXA13 expressions in liver hepatocellular carcinoma (LIHC) were analyzed by starBase, and then the miR-369-5p expression in HCC tissues and cells was detected by quantitative real-time PCR. Subsequently, miR-369-5p mimic was transfected into HCC cells and then its effects on cell activities were evaluated by cell counting kit-8, colony formation, wound healing, transwell assays, respectively. Expressions of epithelial-mesenchymal transition (EMT)-related genes were determined by western blot. The targeting relationship between miR-369-5p and HOXA13 was predicted by Targetscan and verified by dual-luciferase reporter assay. Pearson correlation test was used to analyze the correlation between HOXA13 and miR-369-5p. The above assays were experimented again to investigate the effects of HOXA13 on biological activity and EMT of HCC cells. MiR-369-5p expression was down-regulated and HOXA13 expression was up-regulated in LIHC. MiR-369-5p targeted HOXA13 and the expression of miR-369-5p was negatively correlated with the HOXA13 expression. MiR-369-5p inhibited the viability, proliferation, migration and invasion of HCC cells, increased E-cadherin level and decreased N-cadherin and Vimentin expressions. Concurrently, HOXA13 overexpression could counteract the effects of miR-369-5p on biological activity and EMT-related biomarkers of HCC cells. To conclude, miR-369-5p inhibits the viability, proliferation, migration and invasion of HCC cells by repressing the expression of HOXA13.

Islet transplantation into brown adipose tissue can delay immune rejection.

Type 1 diabetes is an autoimmune disease characterized by insulin-producing ß cell destruction. Although islet transplantation restores euglycemia and improves patient outcomes, an ideal transplant site remains elusive. Brown adipose tissue (BAT) has a highly vascularized and antiinflammatory microenvironment. Because these tissue features can promote islet graft survival, we hypothesized that islets transplanted into BAT will maintain islet graft and BAT function while delaying immune-mediated rejection. We transplanted syngeneic and allogeneic islets into BAT or under the kidney capsule of streptozotocin-induced diabetic NOD.Rag and NOD mice to investigate islet graft function, BAT function, metabolism, and immune-mediated rejection. Islet grafts within BAT restored euglycemia similarly to kidney capsule controls. Islets transplanted in BAT maintained expression of islet hormones and transcription factors and were vascularized. Compared with those in kidney capsule and euglycemic mock-surgery controls, no differences in glucose or insulin tolerance, thermogenic regulation, or energy expenditure were observed with islet grafts in BAT. Immune profiling of BAT revealed enriched antiinflammatory macrophages and T cells. Compared with the kidney capsule control, there were significant delays in autoimmune and allograft rejection of islets transplanted in BAT, possibly due to increased antiinflammatory immune populations. Our data support BAT as an alternative islet transplant site that may improve graft survival.

Hepatocyte Nuclear Factor 4-α (HNF4α) controls the insulin resistance-induced pancreatic ß-cell mass expansion.

BACKGROUND: Regardless of the etiology, any type of DM presents a reduction of insulin-secreting cell mass, so it is important to investigate pathways that induce the increase of this cell mass. AIM: Based on the fact that (1) HNF4α is crucial for ß-cell proliferation, (2) DEX-induced IR promotes ß-cell mass expansion, and (3) the stimulation of ß-cell mass expansion may be an important target for DM therapies, we aimed to investigate whether DEX-induced proliferation of ß pancreatic cells is dependent on HNF4α. METHODS: We used WildType (WT) and Knockout (KO) mice for HNF4-α, treated or not with 100 mg/Kg/day of DEX, for 5 consecutive days. One day after the last injection of DEX the IR was confirmed by ipITT and the mice were euthanized for pancreas removal. RESULTS: In comparison to WT, KO mice presented increased glucose tolerance, lower fasting glucose and increased glucose-stimulates insulin secretion (GSIS). DEX induced IR in both KO and WT mice. In addition, DEX-induced ß-cell mass expansion and an increase in the Ki67 immunostaining were observed only in WT mice, evidencing that IR-induced ß-cell mass expansion is dependent on HNF4α. Also, we observed that DEX-treatment, in an HNF4α-dependent way, promoted an increase in PDX1, PAX4 and NGN3 gene expression. CONCLUSIONS: Our results strongly suggest that DEX-induced IR promotes ß-cell mass expansion through processes of proliferation and neogenesis that depend on the HNF4α activity, pointing to HNF4α as a possible therapeutic target in DM treatment.

A Systematic Review on HOX Genes as Potential Biomarkers in Colorectal Cancer: An Emerging Role of HOXB9.

Emerging evidence shows that Homeobox (HOX) genes are important in carcinogenesis, and their dysregulation has been linked with metastatic potential and poor prognosis. This review (PROSPERO-CRD42020190953) aims to systematically investigate the role of HOX genes as biomarkers in CRC and the impact of their modulation on tumour growth and progression. The MEDLINE, EMBASE, Web of Science and Cochrane databases were searched for eligible studies exploring two research questions: (a) the clinicopathological and prognostic significance of HOX dysregulation in patients with CRC and (b) the functional role of HOX genes in CRC progression. Twenty-five studies enrolling 3003 CRC patients, showed that aberrant expression of HOX proteins was significantly related to tumour depth, nodal invasion, distant metastases, advanced stage and poor prognosis. A post-hoc meta-analysis on HOXB9 showed that its overexpression was significantly associated with the presence of distant metastases (pooled OR 4.14, 95% CI 1.64-10.43, I2 = 0%, p = 0.003). Twenty-two preclinical studies showed that HOX proteins are crucially related to tumour growth and metastatic potential by affecting cell proliferation and altering the expression of epithelial-mesenchymal transition modulators. In conclusion, HOX proteins may play vital roles in CRC progression and are associated with overall survival. HOXB9 may be a critical transcription factor in CRC.

The Potential Roles of Dec1 and Dec2 in Periodontal Inflammation.

Periodontal inflammation is a common inflammatory disease associated with chronic inflammation that can ultimately lead to alveolar attachment loss and bone destruction. Understanding autophagy and pyroptosis has suggested their significant roles in inflammation. In recent years, studies of differentiated embryo-chondrocyte expressed genes 1 and 2 (Dec1 and Dec2) have shown that they play important functions in autophagy and in pyroptosis, which contribute to the onset of periodontal inflammation. In this review, we summarize recent studies on the roles of clock genes, including Dec1 and Dec2, that are related to periodontal inflammation and other diseases.

Mutations and variants of ONECUT1 in diabetes.

Genes involved in distinct diabetes types suggest shared disease mechanisms. Here we show that One Cut Homeobox 1 (ONECUT1) mutations cause monogenic recessive syndromic diabetes in two unrelated patients, characterized by intrauterine growth retardation, pancreas hypoplasia and gallbladder agenesis/hypoplasia, and early-onset diabetes in heterozygous relatives. Heterozygous carriers of rare coding variants of ONECUT1 define a distinctive subgroup of diabetic patients with early-onset, nonautoimmune diabetes, who respond well to diabetes treatment. In addition, common regulatory ONECUT1 variants are associated with multifactorial type 2 diabetes. Directed differentiation of human pluripotent stem cells revealed that loss of ONECUT1 impairs pancreatic progenitor formation and a subsequent endocrine program. Loss of ONECUT1 altered transcription factor binding and enhancer activity and NKX2.2/NKX6.1 expression in pancreatic progenitor cells. Collectively, we demonstrate that ONECUT1 controls a transcriptional and epigenetic machinery regulating endocrine development, involved in a spectrum of diabetes, encompassing monogenic (recessive and dominant) as well as multifactorial inheritance. Our findings highlight the broad contribution of ONECUT1 in diabetes pathogenesis, marking an important step toward precision diabetes medicine.

Increased NKX6.1 expression and decreased ARX expression in alpha cells accompany reduced beta-cell volume in human subjects.

Pancreatic islet cells have plasticity, such as the abilities to dedifferentiate and transdifferentiate. Islet cell conversion to other characteristic cell is largely determined by transcription factors, but significance of expression patterns of these transcription factors in human islet cells remained unclear. Here, we present the NKX6.1-positive ratio of glucagon-positive cells (NKX6.1+/GCG+ ratio) and the ARX-negative ratio of glucagon-positive cells (ARX-/GCG+ ratio) in 34 patients who were not administered antidiabetic agents. Both of NKX6.1+/GCG+ ratio and ARX-/GCG+ ratio negatively associated with relative beta cell area. And these ratios did not have significant correlation with other parameters including age, body mass index, hemoglobin A1c, fasting plasma glucose level or relative alpha-cell area. Our data demonstrate that these expression ratios of transcription factors in glucagon-positive cells closely correlate with the reduction of beta-cell volume in human pancreas.

Nkx6.1 enhances neural stem cell activation and attenuates glial scar formation and neuroinflammation in the adult injured spinal cord.

Nkx6.1 plays an essential role during the embryonic development of the spinal cord. However, its role in the adult and injured spinal cord is not well understood. Here we show that lentivirus-mediated Nkx6.1 expression in the adult injured mouse spinal cord promotes cell proliferation and activation of endogenous neural stem/progenitor cells (NSPCs) at the acute phase of injury. In the chronic phase, Nkx6.1 increases the number of interneurons, reduces the number of reactive astrocytes, minimizes glial scar formation, and represses neuroinflammation. Transcriptomic analysis reveals that Nkx6.1 upregulates the sequential expression of genes involved in cell proliferation, neural differentiation, and Notch signaling pathway, downregulates genes and pathways involved in neuroinflammation, reactive astrocyte activation, and glial scar formation. Together, our findings support the potential role of Nkx6.1 in neural regeneration in the adult injured spinal cord.

Nkx2-2 expressing taste cells in endoderm-derived taste papillae are committed to the type III lineage.

In mammals, multiple cell-signaling pathways and transcription factors regulate development of the embryonic taste system and turnover of taste cells in the adult stage. Using single-cell RNA-Seq of mouse taste cells, we found that the homeobox-containing transcription factor Nkx2-2, a target of the Sonic Hedgehog pathway and a key regulator of the development and regeneration of multiple cell types in the body, is highly expressed in type III taste cells but not in type II or taste stem cells. Using in situ hybridization and immunostaining, we confirmed that Nkx2-2 is expressed specifically in type III taste cells in the endoderm-derived circumvallate and foliate taste papillae but not in the ectoderm-derived fungiform papillae. Lineage tracing revealed that Nkx2-2-expressing cells differentiate into type III, but not type II or type I cells in circumvallate and foliate papillae. Neonatal Nkx2-2-knockout mice did not express key type III taste cell marker genes, while the expression of type II and type I taste cell marker genes were unaffected in these mice. Our findings indicate that Nkx2-2-expressing cells are committed to the type III lineage and that Nkx2-2 may be critical for the development of type III taste cells in the posterior tongue, thus illustrating a key difference in the mechanism of type III cell lineage specification between ectoderm- and endoderm-derived taste fields.

Comparison of the rabbit and human corneal endothelial proteomes regarding proliferative capacity.

The shortage of human donor corneas has raised important concerns about engineering of corneal endothelial cells (CECs) for clinical use. However, due to the limited proliferative capacity of human CECs, driving them into proliferation and regeneration may be difficult. Unlike human CECs, rabbit CECs have a marked proliferative capacity. To clarify the potential reason for this difference, we analysed the proteomes of four human corneal endothelium samples and four rabbit corneal endothelium samples with quantitative label-free proteomics and downstream analysis. We discovered that vitamin and selenocompound metabolism and some signaling pathways such as NF-kappa B signaling pathway differed between the samples. Moreover, TGFß, PITX2 and keratocan were distinctively expressed in rabbit samples, which might be associated with active proliferation in rabbit CECs. This study illustrates the proteomic differences between human and rabbit CECs and might promote CEC engineering strategies.

Structural characteristics of coiled-coil regions in AF10-DOT1L and AF10-inhibitory peptide complex.

The interaction of the solo H3K79 methyltransferase DOT1-like (DOT1L) and its regulatory factor ALL1-fused gene from chromosome 10 protein (AF10) is crucial for the transcription of developmental genes such as HOXA in acute leukemia. The octapeptide motif and leucine zipper region of AF10 is responsible for binding DOT1L and catalyzing H3K79 monomethylation to demethylation. However, the characteristics of the mechanism between DOT1L and AF10 are not clear. Here, we present the crystal structures of coiled-coil regions of DOT1L-AF10 and AF10-inhibitory peptide, demonstrating the inhibitory peptide could form a compact complex with AF10 via a different recognition pattern. Furthermore, an inhibitory peptide with structure-based optimization is identified and decreases the HOXA gene expression in a human cell line. Our studies provide an innovative pharmacologic basis for therapeutic intervention in leukemia.

Transcription Factor VAX1 Regulates the Regional Specification of the Subpallium Through Repressing Gsx2.

Specification of the progenitors' regional identity is a pivotal step during development of the cerebral cortex and basal ganglia. The molecular mechanisms underlying progenitor regionalization, however, are poorly understood. Here we showed that the transcription factor Vax1 was highly expressed in the developing subpallium. In its absence, the RNA-Seq analysis, in situ RNA hybridization, and immunofluorescence staining results showed that the cell proliferation was increased in the subpallium, but the neuronal differentiation was blocked. Moreover, the dLGE expands ventrally, and the vLGE, MGE, and septum get smaller. Finally, overexpressed VAX1 in the LGE progenitors strongly inhibits Gsx2 expression. Taken together, our findings show that Vax1 is crucial for subpallium regionalization by repressing Gsx2.

Genetic impacts on thermostability of onco-lncRNA HOTAIR during the development and progression of endometriosis.

HOTAIR is a well-known long non-coding RNA (lncRNA) involved in various cellular signaling, whereas its functional impacts on endometriosis development are still largely unknown. To this end, six potential functional single nucleotide polymorphisms (SNPs) in HOTAIR, with minor allele frequencies more than 10% in Han population and altered net energy of RNA structures larger than 0.5 kcal/mol, were selected for genotyping study. The study included 207 endometriosis patients and 200 healthy women. Genetic substitutions at rs1838169 and rs17720428 were frequently found in endometriosis patients, and rs1838169 showed statistical significance (p = 0.0174). The G-G (rs1838169-rs17720428) haplotype showed the most significant association with endometriosis (p < 0.0001) with enhanced HOTAIR stability, and patients who harbor such haplotype tended to show higher CA125. Data mining further revealed higher mRNA HOTAIR levels in the endometria of patients with severe endometriosis which consistently showed reduced HOXD10 and HOXA5 levels. HOTAIR knockdown with specific shRNAs down-regulated cell proliferation and migration with the induction of HOXD10 and HOXA5 expression in human ovarian clear cancer cells. Our study therefore provided evidence to indicate a prominent role of HOTAIR in promoting endometriosis, which could be used as a potential target for clinical applications.

Hematopoietically-expressed homeobox protein HHEX regulates adipogenesis in preadipocytes.

Obesity is a key health problem and is associated with a high risk of type 2 diabetes and other metabolic diseases. Increased weight as well as dysregulation of adipocyte homeostasis are the main drivers of obesity. Pathological adipogenesis plays a central role in obesity-related complications such as type 2 diabetes, hypertension and others. Thus, an understanding of the molecular mechanisms involved in physiological and pathogenic adipogenesis can help to develop new strategies to prevent or cure obesity and related diseases. Previously, genetic polymorphisms in the HHEX gene that encodes the homeobox transcription factor HEX (PRH) were found to be associated with type 2 diabetes and high body mass index at birth by GWAS in distinct human populations. To understand whether HHEX has a regulatory function in adipogenesis, we performed RNAi-mediated knockdown of Hhex in preadipocyte cell line 3T3-L1 in vitro, and studied changes in the efficacy of adipogenesis. We found that Hhex knockdown blocks adipogenesis in preadipocytes in a dose-dependent manner and leads to a significant decrease of PPAR-gamma protein - the main regulator of adipogenesis. We also propose that Hhex can play an important role in adipocyte differentiation by affecting the level of the PPAR-gamma protein. Our study supports the claim that Hhex plays an important role in adipocyte differentiation program and can contribute to fat tissue homeostasis.

The Transcription Factor Shox2 Shapes Neuron Firing Properties and Suppresses Seizures by Regulation of Key Ion Channels in Thalamocortical Neurons.

Thalamocortical neurons (TCNs) play a critical role in the maintenance of thalamocortical oscillations, dysregulation of which can result in certain types of seizures. Precise control over firing rates of TCNs is foundational to these oscillations, yet the transcriptional mechanisms that constrain these firing rates remain elusive. We hypothesized that Shox2 is a transcriptional regulator of ion channels important for TCN function and that loss of Shox2 alters firing frequency and activity, ultimately perturbing thalamocortical oscillations into an epilepsy-prone state. In this study, we used RNA sequencing and quantitative PCR of control and Shox2 knockout mice to determine Shox2-affected genes and revealed a network of ion channel genes important for neuronal firing properties. Protein regulation was confirmed by Western blotting, and electrophysiological recordings showed that Shox2 KO impacted the firing properties of a subpopulation of TCNs. Computational modeling showed that disruption of these conductances in a manner similar to Shox2's effects modulated frequency of oscillations and could convert sleep spindles to near spike and wave activity, which are a hallmark for absence epilepsy. Finally, Shox2 KO mice were more susceptible to pilocarpine-induced seizures. Overall, these results reveal Shox2 as a transcription factor important for TCN function in adult mouse thalamus.

IRX3 Overexpression Enhances Ucp1 Expression In Vivo.

Objective: The Iroquois homeobox 3 (IRX3) gene was recently reported to be a functional downstream target of a common polymorphism in the FTO gene, which encodes an obesity-associated protein; however, the role of IRX3 in energy expenditure remains unclear. Studies have revealed that the overexpression of a dominant-negative form of IRX3 in the mouse hypothalamus and adipose tissue promoted energy expenditure by enhancing brown/browning activities. Meanwhile, we and others recently demonstrated that IRX3 knockdown impaired the browning program of primary preadipocytes in vitro. In this study, we aimed to further clarify the effects of overexpressing human IRX3 (hIRX3) on brown/beige adipose tissues in vivo. Methods: Brown/beige adipocyte-specific hIRX3-overexpressing mice were generated and the browning program of white adipose tissues was induced by both chronic cold stimulation and CL316,243 injection. Body weight, fat mass, lean mass, and energy expenditure were measured, while morphological changes and the expression of thermogenesis-related genes in adipose tissue were analyzed. Moreover, the browning capacity of primary preadipocytes derived from hIRX3-overexpressing mice was assessed. RNA sequencing was also employed to investigate the effect of hIRX3 on the expression of thermogenesis-related genes. Results: hIRX3 overexpression in embryonic brown/beige adipose tissues (Rosa26hIRX3 ;Ucp1-Cre) led to increased energy expenditure, decreased fat mass, and a lean body phenotype. After acute cold exposure or CL316,243 stimulation, brown/beige tissue hIRX3-overexpressing mice showed an increase in Ucp1 expression. Consistent with this, induced hIRX3 overexpression in adult mice (Rosa26hIRX3 ;Ucp1-CreERT2) also promoted a moderate increase in Ucp1 expression. Ex vitro experiments further revealed that hIRX3 overexpression induced by Ucp1-driven Cre recombinase activity upregulated brown/beige adipocytes Ucp1 expression and oxygen consumption rate (OCR). RNA sequencing analyses indicated that hIRX3 overexpression in brown adipocytes enhanced brown fat cell differentiation, glycolysis, and gluconeogenesis. Conclusion: Consistent with the in vitro findings, brown/beige adipocyte-specific overexpression of hIRX3 promoted Ucp1 expression and thermogenesis, while reducing fat mass.

DLX6 Antisense RNA 1 Modulates Glucose Metabolism and Cell Growth in Gastric Cancer by Targeting microRNA-4290.

BACKGROUND: Gastric cancer (GC) is one of the most commonly diagnosed malignancy worldwide. DLX6 antisense RNA 1 (DLX6-AS1) is a long noncoding RNA (lncRNA) that exhibits oncogenic effects on multiple human carcinomas. AIMS: This study aimed to investigate the regulatory effect of DLX6-AS1 in GC progression. METHODS: The expression of DLX6-AS1 in GC tissues and cell lines was examined. The cell viability, number of clones, and apoptosis, aerobic glycolysis, and mitochondrial respiration was assessed. The effect of DLX6-AS1 on tumor growth in nude mice was also evaluated. RESULTS: DLX6-AS1 was overexpressed in GC tissues and cell lines. DLX6-AS1 knockdown by short hairpin RNA (shRNA) significantly inhibited cell viability and colony formation, and induced apoptosis. DLX6-AS1 silencing impaired aerobic glycolysis but stimulated mitochondrial respiration in GC cells. miR-4290 was confirmed as a downstream target of DLX6-AS1, and their expression levels were inversely correlated. GC cells expressing sh-DLX6-AS1 showed significantly lower level of 3-phosphoinositide-dependent protein kinase 1 (PDK1), a target of miR-4290, compared to cells expressing control shRNA. In addition, the suppressed GC cell malignancy upon DLX6-AS1 knockdown could be prominently reversed by PDK1 overexpression. Meanwhile, PDK1 overexpression enhanced aerobic glycolysis but repressed mitochondrial respiration under sh-DLX6-AS1 treatment. Furthermore, DLX6-AS1 knockdown significantly delayed the tumor growth in a mouse xenograft model inoculated with GC cells. CONCLUSIONS: LncRNA DLX6-AS1 regulated tumor growth and aerobic glycolysis in GC by targeting miR-4290 and PDK1, suggesting DLX6-AS1 might serve as a novel potential therapeutic target for GC treatment from bench to clinic.