The oncogenic role and regulatory mechanism of ACAA2 in human ovarian cancer.

Acetyl-CoAacyltransferase2 (ACAA2) is a key enzyme in the fatty acid oxidation pathway that catalyzes the final step of mitochondrial ß oxidation, which plays an important role in fatty acid metabolism. The expression of ACAA2 is closely related to the occurrence and malignant progression of tumors. However, the function of ACAA2 in ovarian cancer is unclear. The expression level and prognostic value of ACAA2 were analyzed by databases. Gain and loss of function were carried out to explore the function of ACAA2 in ovarian cancer. RNA-seq and bioinformatics methods were applied to illustrate the regulatory mechanism of ACAA2. ACAA2 overexpression promoted the growth, proliferation, migration, and invasion of ovarian cancer, and ACAA2 knockdown inhibited the malignant progression of ovarian cancer as well as the ability of subcutaneous tumor formation in nude mice. At the same time, we found that OGT can induce glycosylation modification of ACAA2 and regulate the karyoplasmic distribution of ACAA2. OGT plays a vital role in ovarian cancer as a function of oncogenes. In addition, through RNA-seq sequencing, we found that ACAA2 regulates the expression of DIXDC1. ACAA2 regulated the malignant progression of ovarian cancer through the WNT/ß-Catenin signaling pathway probably. ACAA2 is an oncogene in ovarian cancer and has the potential to be a target for ovarian cancer therapy.

DIX domain containing 1 (DIXDC1) modulates VEGFR2 level in vasculatures to regulate embryonic and postnatal retina angiogenesis.

BACKGROUND: In sprouting angiogenesis, VEGFR2 level is regulated via a fine-tuned process involving various signaling pathways. Other than VEGF/VEGFR2 signaling pathway, Wnt/ ß-catenin signaling is also important in vascular development. However, the crosstalk between these two signaling pathways is still unknown to date. In this study, we aimed to investigate the role of DIX domain containing 1 (DIXDC1) in vasculature, facilitating the crosstalk between VEGF/VEGFR2 and Wnt/ ß-catenin signaling pathways. RESULTS: In mice, DIXDC1 deficiency delayed angiogenesis at the embryonic stage and suppressed neovascularization at the neonatal stage. DIXDC1 knockdown inhibited VEGF-induced angiogenesis in endothelial cells in vitro by downregulating VEGFR2 expression. DIXDC1 bound Dishevelled Segment Polarity Protein 2 (Dvl2) and polymerized Dvl2 stabilizing VEGFR2 protein via its direct interaction. The complex formation and stability of VEGFR2 was potentiated by Wnt signaling. Moreover, hypoxia elevated DIXDC1 expression and likely modulated both canonical Wnt/ß-catenin signaling and VEGFR2 stability in vasculatures. Pathological angiogenesis in DIXDC1 knockout mice was decreased significantly in oxygen-induced retinopathy (OIR) and in wound healing models. These results suggest that DIXDC1 is an important factor in developmental and pathological angiogenesis. CONCLUSION: We have identified DIXDC1 as an important factor in early vascular development. These results suggest that DIXDC1 represents a novel regulator of sprouting angiogenesis that links Wnt signaling and VEGFR2 stability and may have a potential role in pathological neovascularization.

Proteomic Analysis Reveals Autism-Associated Gene DIXDC1 Regulates Proteins Associated with Mitochondrial Organization and Function.

DIX-domain containing 1 (Dixdc1) is an important regulator of neuronal development including cortical neurogenesis, neuronal migration and synaptic connectivity, and sequence variants in the gene have been linked to autism spectrum disorders (ASDs). Previous studies indicate that Dixdc1 controls neurogenesis through Wnt signaling, whereas its regulation of dendrite and synapse development requires Wnt and cytoskeletal signaling. However, the prediction of these signaling pathways is primarily based on the structure of Dixdc1. Given the role of Dixdc1 in neural development and brain disorders, we hypothesized that Dixdc1 may regulate additional signaling pathways in the brain. We performed transcriptomic and proteomic analyses of Dixdc1 KO mouse cortices to reveal such alterations. We found that transcriptomic approaches do not yield any novel findings about the downstream impacts of Dixdc1. In comparison, our proteomic approach reveals that several important mitochondrial proteins are significantly dysregulated in the absence of Dixdc1, suggesting a novel function of Dixdc1.

Inhibition of DIXDC1 by microRNA-1271 suppresses the proliferation and invasion of prostate cancer cells.

Disheveled-Axin domain containing 1 (DIXDC1) is involved in the development and progression of multiple cancers. However, the function significance of DIXDC1 in prostate cancer remains unclear. In this study, we investigated the function of DIXDC1 in prostate cancer and the regulation of DIXDC1 by microRNAs (miRNAs). We found that DIXDC1 was highly expressed in prostate cancer cells. Knockdown of DIXDC1 by small interfering RNAs markedly suppressed proliferation, invasion and Wnt signaling in prostate cancer cells. DIXDC1 was identified as a target gene of miR-1271 by bioinformatics analysis, dual-luciferase reporter assay, real-time quantitative polymerase chain reaction and Western blot analysis. Furthermore, DIXDC1 expression was inversely correlated with miR-1271 expression in prostate cancer tissues. The overexpression of miR-1271 significantly inhibited proliferation, invasion and Wnt signaling in prostate cancer cells. However, the inhibition of miR-1271 exhibits the opposite effects. Moreover, the overexpression of DIXDC1 significantly reversed the inhibitory effects of miR-1271 overexpression. Taken together, our results suggest that DIXDC1 plays an important role in regulating prostate cancer cell proliferation and invasion. Targeting DIXDC1 by miR-1271 may be a promising therapeutic strategy for prostate cancer.

Knockdown of DIXDC1 Inhibits the Proliferation and Migration of Human Glioma Cells.

DIX domain containing 1 (DIXDC1), the human homolog of coiled-coil-DIX1 (Ccd1), is a positive regulator of Wnt signaling pathway. Recently, it was found to act as a candidate oncogene in colon cancer, non-small-cell lung cancer, and gastric cancer. In this study, we aimed to investigate the clinical significance of DIXDC1 expression in human glioma and its biological function in glioma cells. Western blot and immunohistochemistry analysis showed that DIXDC1 was overexpressed in glioma tissues and glioma cell lines. The expression level of DIXDC1 was evidently linked to glioma pathological grade and Ki-67 expression. Kaplan-Meier curve showed that high expression of DIXDC1 may lead to poor outcome of glioma patients. Serum starvation and refeeding assay indicated that the expression of DIXDC1 was associated with cell cycle. To determine whether DIXDC1 could regulate the proliferation and migration of glioma cells, we transfected glioma cells with interfering RNA-targeting DIXDC1; investigated cell proliferation with Cell Counting Kit (CCK)-8, flow cytometry assays, and colony formation analyses; and investigated cell migration with wound healing assays and transwell assays. According to our data, knockdown of DIXDC1 significantly inhibited proliferation and migration of glioma cells. These data implied that DIXDC1 might participate in the development of glioma, suggesting that DIXDC1 can become a potential therapeutic strategy for glioma.

Expression of Dixdc1 and its Role in Astrocyte Proliferation after Traumatic Brain Injury.

DIX domain containing 1 (Dixdc1), a positive regulator of Wnt signaling pathway, is recently reported to play a role in the neurogenesis. However, the distribution and function of Dixdc1 in the central nervous system (CNS) after brain injury are still unclear. We used an acute traumatic brain injury (TBI) model in adult rats to investigate whether Dixdc1 is involved in CNS injury and repair. Western blot analysis and immunohistochemistry showed a time-dependent up-regulation of Dixdc1 expression in ipsilateral cortex after TBI. Double immunofluorescent staining indicated a colocalization of Dixdc1 with astrocytes and neurons. Moreover, we detected a colocalization of Ki-67, a cell proliferation marker with GFAP and Dixdc1 after TBI. In primary cultured astrocytes stimulated with lipopolysaccharide, we found enhanced expression of Dixdc1 in parallel with up-regulation of Ki-67 and cyclin A, another cell proliferation marker. In addition, knockdown of Dixdc1 expression in primary astrocytes with Dixdc1-specific siRNA transfection induced G0/G1 arrest of cell cycle and significantly decreased cell proliferation. In conclusion, all these data suggest that up-regulation of Dixdc1 protein expression is potentially involved in astrocyte proliferation after traumatic brain injury in the rat.

Dixdc1 targets CyclinD1 and p21 via PI3K pathway activation to promote Schwann cell proliferation after sciatic nerve crush.

Dixdc1 (DIX domain containing-1), the mammalian homolog of Ccd1 (Coiled-coil-Dishevelled-Axin1), is a protein containing a coiled-coil domain and a Dishevelled-Axin (DIX) domain. As a novel component of the Wnt pathway, Dixdc1 has been reported to be able to promote neural progenitor proliferation and neuronal differentiation via Wnt/ß-catenin signaling. But there still remains something unknown about Dixdc1 distribution and functions in the lesion and regeneration of the peripheral nervous system (PNS), so we tried to investigate dynamic changes of Dixdc1 expression in a rat sciatic nerve crush (SNC) model in this study. First of all, we detected SNC-induced increased levels of Dixdc1 in Schwann cells and interestingly identified parallel expression of PCNA (proliferation cell nuclear antigen) with Dixdc1. Besides, we observed up-regulated Dixdc1 during the process of TNF-α-induced Schwann cell proliferation. Also, we discovered that Dixdc1 could promote G1-S phase transition accompanied with the up-regulation of CyclinD1 and down-regulation of p21. More importantly, enhanced effects of Dixdc1 on cell proliferation were confirmed to be associated with PI3K activation. Not only blocking of the PI3K but Dixdc1 knockdown led to significantly decreased ability for proliferation, as well as down-regulation of CyclinD1 and up-regulation of p21. In summary, these data demonstrated that Dixdc1 might participate in Schwann cell proliferation by targeting CyclinD1 and p21 at least partially through the PI3K/AKT activation.

DIXDC1 activates the Wnt signaling pathway and promotes gastric cancer cell invasion and metastasis.

DIXDC1 (Dishevelled-Axin domain containing 1) is a DIX (Dishevelled-Axin) domain-possessing protein that promotes colon cancer cell proliferation and increases the invasion and migration ability of non-small-cell lung cancer via the PI3K pathway. As a positive regulator of the Wnt/ß-catenin pathway, the biological role of DIXDC1 in human gastric cancer and the relationship between DIXDC1 and the Wnt pathway are unclear. In the current study, the upregulation of DIXDC1 was detected in gastric cancer and was associated with advanced TNM stage cancer, lymph node metastasis, and poor prognosis. We also found that the overexpression of DIXDC1 could promote the invasion and migration of gastric cancer cells. The upregulation of MMPs and the downregulation of E-cadherin were found to be involved in the process. DIXDC1 enhanced ß-catenin nuclear accumulation, which activated the Wnt pathway. Additionally, the inhibition of ß-catenin in DIXDC1-overexpressing cells reversed the metastasis promotion effects of DIXDC1. These results demonstrate that the expression of DIXDC1 is associated with poor prognosis of gastric cancer patients and that DIXDC1 promotes gastric cancer invasion and metastasis through the activation of the Wnt pathway; E-cadherin and MMPs are also involved in this process. © 2015 Wiley Periodicals, Inc.

Downregulated expression of DIXDC1 in hepatocellular carcinoma and its correlation with prognosis.

Dishevelled-Axin domain containing 1 (DIXDC1) is a DIX (Dishevelled-Axin) domain possessing protein that acts as a positive regulator of the Wnt pathway. Although DIXDC1 has been investigated in several cancers, it has not yet been studied in human hepatocellular carcinoma (HCC). The purpose of the current study was to investigate the expression pattern of DIXDC1 and assess the clinical significance of DIXDC1 expression in HCC patients. Data containing three independent investigations from Oncomine database demonstrated that DIXDC1 mRNA was downregulated in HCC compared with matched non-cancerous tissues. Similar results were also obtained in 25 paired HCC tissues and corresponding non-cancerous tissues by qPCR and Western blot analysis. Additionally, another independent set of 140 pairs of HCC specimens was evaluated for DIXDC1 expression by IHC and demonstrated that reduced expression of DIXDC1 in 50.7 % (71/140) of HCC tissues was significantly correlated with tumor size (p = 0.024), tumor differentiation (p < 0.001), tumor thrombi (p = 0.019), TNM stage (p = 0.019), and BCLC stage (p = 0.008). Importantly, Kaplan-Meier survival and Cox regression analyses were executed to evaluate the prognosis of HCC patients and found that DIXDC1 protein expression was one of the independent prognostic factors for overall survival of HCC patients.

Upregulated expression of DIXDC1 in intestinal-type gastric carcinoma: co-localization with ß-catenin and correlation with poor prognosis.

BACKGROUND: DIXDC1 (Dishevelled-Axin domain containing 1) is a positive regulator of the Wnt pathway. In the field of cancer research, the role of DIXDC1 is unclear. Our previous in vitro study showed that DIXDC1 enhances ß-catenin nuclear accumulation in gastric cancer cell lines. The aim of this study was to detect the expression of DIXDC1 in different histological subtypes of gastric carcinoma and to evaluate the correlation between the expression of DIXDC1 and ß-catenin localization and clinicopathological parameters, including patients' survival. METHODS: Immunohistochemical staining was performed to characterize the expression of DIXDC1 and ß-catenin in archived materials from 259 cases of gastric carcinoma. The χ2 test and the Fisher's test were used to analyze correlations between DIXDC1 expression, ß-catenin localization, and clinicopathological parameters. Univariate analyses were performed using the Kaplan-Meier method, and the survival difference between groups was assessed by the log-rank test. Multivariate analysis was performed using the Cox proportional hazards regression model. RESULTS: Positive DIXDC1 staining was detected in tumor cells in 123 of 259 (47.5 %) cases. DIXDC1 expression in gastric carcinoma was significantly correlated with the histological intestinal-type (P < 0.001), the depth of tumor invasion (P < 0.001) and the lymph node metastasis (P = 0.006). In the intestinal-type, DIXDC1 was correlated with the nuclear and cytoplasmic ß-catenin expression (P = 0.002). Kaplan-Meier analysis indicated that patients with high DIXDC1 expression had poor disease-specific survival (P < 0.001), especially in the intestinal-type. Moreover, multivariate regression analysis showed that positive expression of DIXDC1 was an independent prognostic predictor of intestinal-type gastric carcinoma. CONCLUSION: Our study indicated that DIXDC1 is a significant independent prognostic indicator in intestinal-type gastric carcinoma that plays an important role in carcinogenesis and progression of gastric carcinoma through the Wnt signaling pathway.

DIXDC1 increases the invasion and migration ability of non-small-cell lung cancer cells via the PI3K-AKT/AP-1 pathway.

DIX domain containing 1 (DIXDC1), is a human homolog of Ccd1, a recently identified DIX domain containing protein in zebrafish. DIXDC1 protein was detected in human colorectal adenocarcinoma tissues and was found to be correlated with a high cell proliferation index. We demonstrated DIXDC1 overexpression in 55% (92/167) of non-small cell lung cancer (NSCLC) cases, compared to adjacent noncancerous lung tissues (P < 0.01). Overexpression of DIXDC1 was associated with lymph node metastasis and more advanced TNM stage (P < 0.001 and P = 0.001, respectively). Kaplan-Meier survival curves and log-rank testing indicated that overexpression of DIXDC1 correlated with worse overall survival in NSCLC (P = 0.031). DIXDC1 was more abundant in seven NSCLC lines than the bronchial cell line HBE, and modulation of its expression regulated AP-1 activity; MMP2, MMP7, and MMP9 protein and mRNA; and invasion ability. Metalloproteinase induction was reversed by PI3K/AKT and AP-1 inhibition. These results suggest DIXDC1 is associated with stage and prognosis in NSCLC, and may promote invasion and migration through PI3K-AKT/AP-1-dependent activation of metalloproteinases.

Quantitative trait loci on chromosomes 9 and 19 modulate AII amacrine cell number in the mouse retina.

Sequence variants modulating gene function or expression affect various heritable traits, including the number of neurons within a population. The present study employed a forward-genetic approach to identify candidate causal genes and their sequence variants controlling the number of one type of retinal neuron, the AII amacrine cell. Data from twenty-six recombinant inbred (RI) strains of mice derived from the parental C57BL/6J (B6/J) and A/J laboratory strains were used to identify genomic loci regulating cell number. Large variation in cell number is present across the RI strains, from a low of ∼57,000 cells to a high of ∼87,000 cells. Quantitative trait locus (QTL) analysis revealed three prospective controlling genomic loci, on Chromosomes (Chrs) 9, 11, and 19, each contributing additive effects that together approach the range of variation observed. Composite interval mapping validated two of these loci, and chromosome substitution strains, in which the A/J genome for Chr 9 or 19 was introgressed on a B6/J genetic background, showed increased numbers of AII amacrine cells as predicted by those two QTL effects. Analysis of the respective genomic loci identified candidate controlling genes defined by their retinal expression, their established biological functions, and by the presence of sequence variants expected to modulate gene function or expression. Two candidate genes, Dtx4 on Chr 19, being a regulator of Notch signaling, and Dixdc1 on Chr 9, a modulator of the WNT-ß-catenin signaling pathway, were explored in further detail. Postnatal overexpression of Dtx4 was found to reduce the frequency of amacrine cells, while Dixdc1 knockout retinas contained an excess of AII amacrine cells. Sequence variants in each gene were identified, being the likely sources of variation in gene expression, ultimately contributing to the final number of AII amacrine cells.

LncRNAs ENST00000499459 and TCONS_00004989 enhance asthma progression in children with house dust mite-induced allergic asthma.

BACKGROUND: Long non-coding RNAs (lncRNAs) have been extensively reported to play critical roles in the pathogenesis of various disease, especially in cancer. However, little is known about the role of lncRNAs in the pathogenesis of pediatric allergic asthma. METHODS: High-throughput sequencing analysis was performed to identify differentially expressed mRNAs and lncRNAs in peripheral blood mononuclear cells (PBMCs) from 3 children with allergic asthma and 3 matched healthy controls. Bioinformatics analysis was used to select candidate lncRNAs and mRNAs that may be involved in the pathogenesis of asthma. Candidate lncRNAs were validated in a larger size of asthma patients and healthy controls. Finally, lncRNAs and molecular pathways associated with the pathogenesis of allergic asthma were identified by competing endogenous RNA (ceRNA) analysis. RESULTS: Five differentially expressed lncRNAs were identified after high-throughput sequencing and verified by real-time PCR. LncRNAs ENST0000631797, TCONS_00004989 and ENST00000499459 were verified to be differentially expressed in allergic asthma. Besides, ENST00000499459/DIXDC1 axis was identified to play a crucial role in allergic asthma after comprehensive ceRNA network analysis. CONCLUSION: ENST00000499459 and TCONS_00004989 are potential biomarkers for house dust mite-induced allergic asthma.

Circular RNA circ_0000423 promotes gastric cancer cell proliferation, migration and invasion via the microR-582-3p/Disheveled-Axin domain containing 1 axis.

For humans, gastric cancer (GC) is a common malignancy. Multiple circular RNAs (circRNAs) have been confirmed to be important cancer-promoting or tumor-suppressive factors. The present study discusses the roles and mechanisms of circ_0000423 in GC development. In this study, circ_0000423 expression in GC patient tissue samples and cell lines was detected via quantitative real-time polymerase chain reaction. Disheveled-Axin domain containing 1 (DIXDC1) expression in GC cells was examined via Western blot. Besides, cell counting kit-8 was utilized for detecting GC cell viability. GC cell migration and invasion were examined through Transwell assays. Bioinformatics and dual-luciferase reporter gene assays were employed to verify the regulatory relationships between microRNA-582-3p (miR-582-3p) and circ_0000423 or DIXDC1. In the present study, we demonstrated that circ_0000423 was highly expressed in GC. Circ_0000423 knockdown suppressed GC cell viability, migration and invasion. Moreover, miR-582-3p was confirmed as a direct target of circ_0000423, and an upstream regulator of DIXDC1. MiR-582-3p inhibition or DIXDC1 overexpression could reverse the above-mentioned effects of knocking down circ_0000423 on GC cells. In conclusion, circ_0000423 facilitates GC progression by modulating the miR-582-3p/DIXDC1 axis.

Suppression of Disheveled-Axin Domain Containing 1 (DIXDC1) by MicroRNA-186 Inhibits the Proliferation and Invasion of Retinoblastoma Cells.

Recent evidence shows that Disheveled-Axin domain containing 1 (DIXDC1) is dysregulated in various cancers. However, the role of DIXDC1 in retinoblastoma (RB) remains unclear. In this study, we aimed to investigate the biological function of DIDXDC1 in RB and the way in which its expression is regulated by microRNAs (miRNAs). We found that DIXDC1 expression was significantly upregulated in RB cell lines. The silencing of DIXDC1 by small interfering RNA (siRNA) significantly inhibited the proliferation, invasion, and Wnt signaling in RB cell lines. Interestingly, DIXDC1 was identified as a target gene of miR-186. The expression of DIXDC1 was negatively regulated by miR-186, and DIXDC1 expression was inversely correlated with miR-186 expression in RB clinical specimens. Overexpression of miR-186 inhibited the proliferation, invasion, and Wnt signaling in RB cell lines. Moreover, overexpression of DIXDC1 markedly reversed the antitumor effect of miR-186. Overall, our results reveal that DIXDC1 functions as a potential oncogene in RB, and inhibiting DIXDC1 by miR-186 suppresses the proliferation and invasion of RB cell lines. Our study suggests that DIXDC1 and miR-186 may serve as novel therapeutic targets for the treatment of RB.

DIXDC1 promotes the growth of acute myeloid leukemia cells by upregulating the Wnt/ß-catenin signaling pathway.

Accumulating evidence suggests that dysregulation of Dishevelled-Axin domain-containing 1 (DIXDC1) is involved in the progression and development of various cancers. However, little is known about the relevance of DIXDC1 in acute myeloid leukemia (AML). In this study, we aimed to investigate the expression status and potential biological function of DIXDC1 in AML. Our results showed that DIXDC1 expression was highly upregulated in AML cell lines and primary AML blasts compared with normal blasts. Knockdown of DIXDC1 by siRNA-mediated gene silencing significantly inhibited proliferation, induced cell cycle arrest, and promoted apoptosis of AML cells in vitro. By contrast, DIXDC1 overexpression promoted proliferation, accelerated cell cycle progression, and reduced apoptosis of AML cells. Moreover, we found that DIXDC1 knockdown decreased the expression of ß-catenin and restricted the activation of Wnt signaling. In addition, DIXDC1 knockdown decreased the expression of Wnt/ß-catenin target genes, including cyclin D1 and c-myc, while DIXDC1 overexpression had the opposite effect. Notably, ß-catenin knockdown partially reversed the oncogenic effect of DIXDC1 in AML cells. Taken together, these results demonstrate that DIXDC1 promotes the growth of AML cells, possibly through upregulating the Wnt/ß-catenin signaling pathway. Our study suggests that DIXDC1 may serve as a potential therapeutic target for the treatment of AML.

MicroRNA-539 inhibits glioma cell proliferation and invasion by targeting DIXDC1.

Dysregulation of microRNAs (miRNAs) has been suggested to contribute to malignant progression of glioma. Previous studies have demonstrated that miR-539 is dysregulated in malignant progression of cancers. However, the potential role and mechanism of miR-539 in the progression of glioma remains unclear. In this study, we aimed to investigate the expression status and functional significance of miR-539 in glioma. We found that miR-539 expression was significantly decreased in glioma cell lines and tissues. Overexpression of miR-539 markedly inhibited glioma cell proliferation and invasion, while miR-539 suppression exhibited the opposite effect. Bioinformatics analysis and dual-luciferase reporter assays showed that miR-539 directly targeted the 3'-untranslated region of Disheveled-axin domain containing 1 (DIXDC1). DIXDC1 expression was negatively regualted by miR-539 overexpression. An inverse correlation between DIXDC1 mRNA expression and miR-539 expression was found in glioma specimens. Furthermore, knockdown of DIXC1 significantly inhibited proliferation, invasion and Wnt signaling in glioma cells. Overexpression of DIXDC1 partially reversed the inhibitory effect of miR-539 on glioma cell proliferation and invasion. Overall, these findings demonstrate that miR-539 inhibits glioma cell proliferation and invasion by targeting DIXDC1. Our study suggests that the miR-539 may serve as a potential target for the clinical diagnosis and treatment of glioma.

DIXDC1 promotes tumor proliferation and cell adhesion mediated drug resistance (CAM-DR) via enhancing p-Akt in Non-Hodgkin's lymphomas.

DIX domain containing 1 (DIXDC1), is a human homolog of Ccd1, a DIX domain containing protein in zebrafish. The present study was undertaken to determine the expression and biologic function of DIXDC1 in Non-Hodgkin's lymphoma (NHL). Clinically, we detected that the expression of DIXDC1 was significantly lower in the indolent lymphomas compared with the progressive lymphomas by immunohistochemistry analysis. Functionally, we found that DIXDC1 could promote cell proliferation via modulating cell cycle progression and PI3K/AKT signaling pathway in NHLs. Moreover, we confirmed that DIXDC1 was involved in the process of lymphoma cell adhesion mediated drug resistance (CAM-DR). Adhesion to fibronectin (FN) or HS-5 up-regulated DIXDC1 expression, and up-regulation of DIXDC1 resulted in an increased expression of p-AKT, which promoted CAM-DR. Our finding supports the role of DIXDC1 in cell proliferation, cell cycle and CAM-DR in NHLs. We propose that inhibition of DIXDC1 expression may be a novel therapeutic approach for NHLs patients, and it may be a target for drug resistance.

Overexpression of DIXDC1 correlates with enhanced cell growth and poor prognosis in human pancreatic ductal adenocarcinoma.

Disheveled-axin (DIX) domain containing 1 (DIXDC1), a protein containing a coiled-coil domain and a DIX domain, is involved in the progression of multiple cancers. However, the role of DIXDC1 in human pancreatic ductal adenocarcinoma (PDAC) remains unclear. In this study, we investigated the role and prognostic value of DIXDC1 in the development of human PDAC. Western blot analysis revealed that DIXDC1 was highly expressed in PDAC tissues and cell lines. Immunohistochemistry on 165 paraffin-embedded sections showed that high expression of DIXDC1 was significantly correlated with tumor size (P = .002), histological differentiation (P = .001), tumor node metastasis (TNM) stage (P = .001), and the proliferation marker Ki-67 (P = .000). Importantly, Kaplan-Meier analysis revealed that high expression of DIXDC1 was obviously correlated with worsened overall survival (P < .001). In vitro, using serum starvation-refeeding experiments, our results suggested that DIXDC1 was up-regulated in proliferating PDAC cells, together with the percentage of cells at the S phase, and was correlated with the expression of cyclin D1. In addition, depletion of DIXDC1 decreased PCNA and cyclin D1 levels. Accordingly, CCK-8, colony formation, and flow cytometry analyses revealed that knocking down DIXDC1 induced growth impairment and G1/S cell cycle arrest in PDAC cells, while overexpression of DIXDC1 led to accelerated cell proliferation and cell cycle progression. On the basis of these results, we propose that DIXDC1 could play an important role in the tumorigenesis of PDAC and serve as a potential therapeutical target to prevent PDAC progression.