RP11-495P10.1 promotes HCC cell proliferation by regulating reprogramming of glucose metabolism and acetylation of the NR4A3 promoter via the PDK1/PDH axis.

The incidence and related death of hepatocellular carcinoma (HCC) have increased over the past decades. However, the molecular mechanisms underlying HCC pathogenesis are not fully understood. Long noncoding RNA (lncRNA) RP11-495P10.1 has been proven to be closely associated with the progression of prostate cancer, but its role and specific mechanism in HCC are still unknown. Here, we identify that RP11-495P10.1 is highly expressed in HCC tissues and cells and contributes to the proliferation of HCC cells. Moreover, this study demonstrates that RP11-495P10.1 affects the proliferation of HCC by negatively regulating the expression of nuclear receptor subfamily 4 group a member 3 (NR4A3). Glycometabolism reprogramming is one of the main characteristics of tumor cells. In this study, we discover that RP11-495P10.1 regulates glycometabolism reprogramming by changing the expression of pyruvate dehydrogenase kinase 1 (PDK1) and pyruvate dehydrogenase (PDH), thus contributing to the proliferation of HCC cells. Furthermore, knockdown of RP11-495P10.1 increases enrichment of H3K27Ac in the promoter of NR4A3 by promoting the activity of PDH and the production of acetyl-CoA, which leads to the increased transcription of NR4A3. Altogether, RP11-495P10.1 promotes HCC cell proliferation by regulating the reprogramming of glucose metabolism and acetylation of the NR4A3 promoter via the PDK1/PDH axis, which provides an lncRNA-oriented therapeutic strategy for the diagnosis and treatment of HCC.

LINC01559 accelerates pancreatic cancer cell proliferation and migration through YAP-mediated pathway.

Pancreatic cancer (PC) is one of the top two most fatal cancers, with the poorest survival rate among all human malignancies. Increasing evidence suggests the involvement of long noncoding RNAs (lncRNAs) in the initiation and progression of various cancers. Herein, we investigated the role of lncRNA LINC01559 in PC. Several online databases indicated that LINC01559 was at a low expression in normal pancreatic tissues but was obviously upregulated in PAAD tissues. Further, our results showed that LINC01559 was stimulated in PC cell lines relative to normal controls. Furthermore, we validated that LINC01559 facilitated PC cell proliferation and migration in vitro. Also, silencing LINC01559 obstructed PC cell growth in vivo. Besides, LINC01559 was revealed to be mainly in the cytoplasm of PC cells and therefore served as a ceRNA of Yes-associated protein (YAP) in PC cells via sponging miR-607. Surprisingly, we also proved that LINC01559 could interact with YAP protein, which might hinder YAP phosphorylation and enhance YAP transcriptional activity in PC cells. Furthermore, we demonstrated that YAP was the downstream effector in LINC01559-regulated PC development. Collectively, our findings unmasked that LINC01559 accelerates PC progression through relying on YAP, providing a new potential target for clinical treatment of patients with PC.

Long Non-Coding MALAT1 Functions as a Competing Endogenous RNA to Regulate Vimentin Expression by Sponging miR-30a-5p in Hepatocellular Carcinoma.

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) has a high morbidity as well as mortality and is believed to be one of the most prevalent cancers worldwide. The long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is involved in numerous cancers, including HCC. This study aimed to explore the role of MALAT1 in HCC progression. METHODS: The expression levels of MALAT1 and Vimentin in HCC tissues and relative pair-matched adjacent normal liver tissues were analyzed by RT-PCR, and immunohistochemistry. Using bioinformatics analysis and dual-luciferase assay, we examined the correlation between MALAT1 and miR-30a-5p. Dual-luciferase assay and western blotting suggested that Vimentin was a target of miR-30a-5p. A wound healing assay and transwell assays were employed to determine the effect of MALAT1 and miR-30a-5p on cell migration and invasion in HCC. RESULTS: Our data demonstrated that the levels of MALAT1 and Vimentin were upregulated in HCC tissues and that miR-30a-5p was a direct target of MALAT1. Silenced MALAT1 and overexpressed miR-30a-5p each inhibited cell migration and invasion. Additionally, dual-luciferase assay and western blotting demonstrated that MALAT1 could competitively sponge miR-30a-5p and thereby regulate Vimentin. CONCLUSION: Our data suggest that MALAT1 acts as an oncogenic lncRNA that promotes HCC migration and invasion. Therefore, the MALAT1-miR-30a-5p-Vimentin axis is a potential therapeutic target and molecular biomarker in HCC.

[Identification of a novel STK11 gene mutation in a family affected with hereditary Peutz-Jeghers syndrome].

OBJECTIVE To explore the genetic basis for a family affected with Peutz-Jeghers syndrome (PJS). METHODS Genomic DNA was extracted from peripheral blood and oral swab samples from the patient and her relatives. Next-generation sequencing (NGS) was used to analyze 106 target genes by capturing the exons and adjacent intronic regions. Suspected pathogenic mutation was verified by NGS. RESULTS A missense STK11 mutation was detected in the proband, which was not reported previously. The mutation has caused substitution of Leucine by Proline. NGS has detected the same mutation in the mother but not among other relatives. CONCLUSION This hereditary case of PJS may be attributed to the missense mutation of the STK11 gene.

Advances and prospects of drug clinical research in colorectal cancer in 2022.

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer death worldwide. Clinical research results have provided more treatment opportunities for CRC patients, showing that an optimal combination of existing drugs and new drugs is needed to mitigate the burden of this disease. In this review, we have summarized recent advances in drug clinical research for CRC in 2022, including chemotherapy, targeted therapy, and immunotherapy, to find opportunities for substantial improvements in drug discovery and clinical development methods.

Long non-coding RNA AC245100.4 activates the PI3K/AKT pathway to promote PCa cell proliferation by elevating PAR2.

Background: Prostate cancer (PCa) is among the most generally diagnosed cancers in males. A long non-coding RNA (lncRNA) called AC245100.4 has been discovered and linked to PCa carcinogenesis. However, its specific and potential mechanism is uncertain in PCa. In this research, we investigated the role of AC245100.4 in cell proliferation and the underlying mechanism in PCa cells. Methods: qRT-PCR assays were utilized to detect AC245100.4 expression and confirm its downstream target. The pathways related to AC245100.4 were identified by RAP-MS. PCa cell proliferation was experimented by Cell Counting Kit-8 and Colony formation assays. Western blot was performed to detect PAR2, AKT, p-AKT, Cyclin D1 and PCNA expression. Results: AC245100.4/PAR2 overexpression promotes PCa cell proliferation and the opposite results are obtained after AC245100.4/PAR2 knockdown. Mechanistically, we found that PAR2 is confirmed as the AC245100.4 downstream target and AC245100.4 promotes PCa cell proliferation by regulating PAR2. AC245100.4 promotes PCa cell proliferation via PI3K/AKT pathway. Rescue assays validated that PAR2 knockdown reversed the impact of AC245100.4 overexpression on increasing p-AKT protein levels. Conclusion: This research revealed that AC245100.4 enhances cell proliferation in PCa cells through modulating the PAR2/PI3K/AKT axis, which may offer novel tumor markers and potential therapeutic targets for PCa.

Cyclosporin A induces cardiomyocyte injury through calcium-sensing receptor-mediated calcium overload.

The aim of this study was to investigate whether Cyclosporin-A (CsA)-induced myocardial injury is mediated by elevating the intracellular calcium concentration ([Ca2+]i) through the Calcium sensing receptor (CaSR). Cultured neonatal rat cardiomyocytes were treated with CsA, with or without pretreatment with the CaSR-specific antagonist NPS2390 or the CaSR-specific agonist gadolinium chloride (GdCI3). At 2 h, 4 h, 6 h and 8 h after CsA treatment, the ultrastructural changes of the cardiomyocytes were observed. In addition, the lactate dehydrogenase (LDH) and creatine kinase (CK) release from the cardiomyocytes, the [Ca2+]i and the level of CaSR expression were determined. With increasing time of CsA treatment, ultrastructural damage of cardimyocytes gradually aggrevated, LDH and CK release and [Ca2+]i also gradually increased. CaSR mRNA and protein expression increased at 4 h after CsA treatment. Compared with CsA treatment alone, pretreatment with NPS2390 lessened the ultrastructural damage of the cardiomyocytes as well as decreased the LDH and CK release, [Ca2+]i and the expression of the CaSR mRNA and protein. Conversely, pretreatment with GdCI3 aggravated the ultrastructural damage of the cardiomyocytes as well as increased LDH and CK release, [Ca2+]i and the expression of the CaSR mRNA and protein. These results demonstrate that CsA induced cardiomyocyte injury in a time-dependent manner. Moreover, CsA-induced cardiomyocyte injury was related to CaSR-mediated intracellular calcium overload. These findings provide new insight into the mechanisms involved in CsA-induced myocardial injury.

Involvement of the calcium-sensing receptor in cyclosporin A-induced cardiomyocyte apoptosis in rats.

In this study, we sought to determine whether the calcium-sensing receptor (CaSR) is involved in Cyclosporin A (CsA)-induced cardiomyocyte apoptosis and identify its signal transduction pathway. Forty Wistar rats were randomly divided into four groups: the control group, the CsA group (CsA 15 mg/kg/day intraperitoneally, i.p.), the GdCl3 group (GdCI3 10 mg/kg, every other day, i.p.), and the CsA + GdCl3 group (CsA 15 mg/kg/day, i.p. and GdCl3 10 mg/kg, every other day, i.p.). The groups were treated for two weeks. Cardiomyocyte apoptosis and injury were observed by light microscopy, electron microscopy and TUNEL staining. CaSR mRNA expression was determined by RT-PCR, and CaSR protein expression was detected by western blot and immunohistochemistry. The protein expression levels of cytochrome c, cleaved caspase-9, cleaved caspase-3, Bax, and Bcl-2 were detected by western blot and immunohistochemistry. CsA increased the expression of CaSR mRNA and protein and enhanced cardiomyocyte apoptosis. GdCl3, a specific activator of CaSR, further enhanced CaSR expression and cardiomyocyte apoptosis and led to the upregulation of cytochrome c, cleaved caspase-9, cleaved caspase-3, and Bax, as well as the downregulation of Bcl-2. The present in vivo study provides further information on CsA-induced cardiomyocyte apoptosis. We determined for the first time that CaSR is involved in CsA-induced cardiomyocyte apoptosis in the rat through the activation of downstream cytochrome c-caspase-3 pathways. Furthermore, we offer evidence that the Bcl-2 family is involved in this process. These findings could provide novel strategies for the prevention and cure of CsA-induced cardiotoxicity.

5-Hydroxymethylcytosine signature in circulating cell-free DNA as a potential diagnostic factor for early-stage colorectal cancer and precancerous adenoma.

Approximately 85% colorectal cancers (CRCs) are thought to evolve through the adenoma-to-carcinoma sequence associated with specific molecular alterations, including the 5-hydroxymethylcytosine (5hmC) signature in circulating cell-free DNA (cfDNA). To explore colorectal disease progression and evaluate the use of cfDNA as a potential diagnostic factor for CRC screening, here, we performed genome-wide 5hmC profiling in plasma cfDNA and tissue genomic DNA (gDNA) acquired from 101 samples (63 plasma and 38 tissues), collected from 21 early-stage CRC patients, 21 AD patients, and 21 healthy controls (HC). The gDNA and cfDNA 5hmC signatures identified in gene bodies and promoter regions in CRC and AD groups were compared with those in HC group. All the differential 5hmC-modified regions (DhMRs) were gathered into four clusters: Disease-enriched, AD-enriched, Disease-lost, and AD-lost, with no overlap. AD-related clusters, AD-enriched and AD-lost, displayed the unique 5hmC signals in AD patients. Disease-enriched and Disease-lost clusters indicated the general 5hmC changes when colorectal lesions occurred. Cancer patients with a confirmable adenoma history segmentally gathered in AD-enriched clusters. KEGG functional enrichment and GO analyses determined distinct differential 5hmC-modified profiles in cfDNA of HC individuals, AD, and CRC patients. All patients had comprehensive 5hmC signatures where Disease-enriched and Disease-lost DhMR clusters demonstrated similar epigenetic modifications, while AD-enriched and AD-lost DhMR clusters indicated complicated subpopulations in adenoma. Analysis of CRC patients with adenoma history showed exclusive 5hmC-gain characteristics, consistent with the 'parallel' evolution hypothesis in adenoma, either developed through the adenoma-to-carcinoma sequence or not. These findings deepen our understanding of colorectal disease and suggest that the 5hmC modifications of different pathological subtypes (cancer patients with or without adenoma history) could be used to screen early-stage CRC and assess adenoma malignancy with large-scale follow-up studies in the future.

Downregulation of miR-146b-5p via iodine involvement repressed papillary thyroid carcinoma cell proliferation.

miR-146b-5p is overexpressed in papillary thyroid carcinoma (PTC) and is thought to be a related diagnostic marker. Previous studies have indicated the effects of iodine on oncogenic activation. However, the effect of iodine on the proliferation of PTC cells and the associated underlying mechanisms remain unclear. We found that miR-146b-5p was downregulated and smad4 was upregulated in patients exposed to high iodine concentration by in situ hybridisation (ISH) and immunohistochemical (IHC). NaI (10-3 M) treatment downregulated miR-146b-5p and upregulated Smad4 in PTC cell lines. Luciferase assay was used to confirm that Smad4 is a target of miR-146b-5p. Furthermore, MTT assay and cell cycle analysis indicated that 10-3 M NaI suppressed cell proliferation and caused G0/G1 phase arrest. Real-time PCR and Western blotting demonstrated that 10-3 M NaI increased p21, p27, and p57 levels and reduced cyclin D1 levels in PTC cells. Our findings suggest that 10-3 M NaI increases Smad4 levels through repression of miR-146b-5p expression, curbing the proliferation in PTC.

miR-124-3p availability is antagonized by LncRNA-MALAT1 for Slug-induced tumor metastasis in hepatocellular carcinoma.

BACKGROUND: As an oncogene, long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) can promote tumor metastasis. Hyperexpression of MALAT1 has been observed in many malignant tumors, including hepatocellular carcinoma (HCC). However, the role and mechanism of MALAT1 in HCC remain unclear. METHODS: Thirty human HCC and paracancerous tissue specimens were collected, and the human hepatoma cell lines Huh7 and HepG2 were cultured according to standard methods. MALAT1 and Snail family zinc finger (Slug) expression were measured by real-time PCR, immunohistochemistry, and western blotting. Luciferase reporter assay and RNA immunoprecipitation (RIP) assay verified the direct interaction between miR-124-3p and Slug(SNAI2) or MALAT1. Wound healing and transwell assays were performed to examine invasion and migration, and a subcutaneous tumor model was established to measure tumor progression in vivo. RESULTS: MALAT1 expression was upregulated in HCC tissues and positively correlated with Slug expression. MALAT1 and miR-124-3p bind directly and reversibly to each other. MALAT1 silencing inhibited cell migration and invasion. miR-124-3p inhibited HCC metastasis by targeting Slug. CONCLUSIONS: MALAT1 regulates Slug through miR-124-3p, affecting HCC cell metastasis. Thus, the MALAT1/miR-124-3p/Slug axis plays an important role in HCC.

CX3CL1 increases invasiveness and metastasis by promoting epithelial-to-mesenchymal transition through the TACE/TGF-α/EGFR pathway in hypoxic androgen-independent prostate cancer cells.

Epithelial-to-mesenchymal transition (EMT) endows cancer cells with enhanced invasive and metastatic potential during cancer progression. Fractalkine, also known as chemokine (C-X3-C motif) ligand 1 (CX3CL1), the only member recognized so far that belongs to the CX3C chemokine subfamily, was reported to participate in the molecular events that regulate cell adhesion, migration and survival of human prostate cancer cells. However, the relationship between CX3CL1 and EMT remains unknown. We treated DU145 and PC-3 cells with CX3CL1 under hypoxic conditions. The migration and invasion abilities of DU145 and PC-3 cells were detected by Transwell assays. Induction of EMT was verified by morphological changes in the DU145 and PC-3 cells and analysis of protein expression of EMT markers such as E-cadherin and vimentin. To identify the involved signaling pathway in CX3CL1-induced EMT, activation of epidermal growth factor receptor (EGFR) was measured using western blot analysis, and Slug expression was detected with or without an EGFR inhibitor prior to CX3CL1 treatment. Concentrations of soluble and total TGF-α in the CX3CL­treated DU145 cells were detected by ELISA. Additionally, we determined the involvement of the TACE/TGF-α/EGFR pathway in CX3CL1­induced EMT using RNA interference and specific inhibitors. CX3CL1 increased the migration and invasiveness of the DU145 and PC-3 cells, and resulted in characteristic alterations of EMT. Our results demonstrated that TACE/TGF-α/EGFR pathway activation and subsequent upregulation of Slug expression were responsible for CX3CL1­induced EMT, and contributed to the migration and inva-sion of prostate cancer cells. Inhibition of TACE/TGF-α/EGFR signaling reversed EMT and led to reduced migration and invasion abilities of the prostate cancer cells. We provide initial evidence that CX3CL1 exposure resulted in EMT occurrence and enhancement of cell migration and invasion through a mechanism involving activation of TACE/TGF-α/EGFR signaling. These findings revealed that CX3CL1 may serve as a new target for the treatment of prostate cancer.

Upregulation of fractalkine contributes to the proliferative response of prostate cancer cells to hypoxia via promoting the G1/S phase transition.

Hypoxia is a common phenomenon in prostate cancer, which leads to cell proliferation and tumor growth. Fractalkine (FKN) is a membrane­bound chemokine, which is implicated in the progression of human prostate cancer and skeletal metastasis. However, the association between FKN and hypoxia­induced prostate cancer cell proliferation remains to be elucidated. The present study demonstrated that hypoxia induced the expression and secretion of FKN in the DU145 prostate cancer cell line. Furthermore, inhibiting the activity of FKN with the anti­FKN FKN­specific antibody markedly inhibited hypoxia­induced DU145 cell proliferation. Under normoxic conditions, DU145 cell proliferation markedly increased following exogenous administration of human recombinant FKN protein, and the increase was significantly alleviated by anti­FKN, indicating the importance of FKN in DU145 cell proliferation. In addition, subsequent determination of cell cycle distribution and expression levels of two core cell cycle regulators, cyclin E and cyclin­dependent kinase (CDK)2, suggested that FKN promoted the G1/S phase transition by upregulating the expression levels of cyclin E and CDK2. The results of the present study demonstrated that hypoxia led to the upregulation of the secretion and expression of FKN, which enhanced cell proliferation by promoting cell cycle progression in the prostate cancer cells. These findings provide evidence of a novel function for FKN, and suggest that FKN may serve as a potential target for treating androgen­independent prostate cancer.

Calcium Ion Flow Permeates Cells through SOCs to Promote Cathode-Directed Galvanotaxis.

Sensing and responding to endogenous electrical fields are important abilities for cells engaged in processes such as embryogenesis, regeneration and wound healing. Many types of cultured cells have been induced to migrate directionally within electrical fields in vitro using a process known as galvanotaxis. The underlying mechanism by which cells sense electrical fields is unknown. In this study, we assembled a polydimethylsiloxane (PDMS) galvanotaxis system and found that mouse fibroblasts and human prostate cancer PC3 cells migrated to the cathode. By comparing the effects of a pulsed direct current, a constant direct current and an anion-exchange membrane on the directed migration of mouse fibroblasts, we found that these cells responded to the ionic flow in the electrical fields. Taken together, the observed effects of the calcium content of the medium, the function of the store-operated calcium channels (SOCs) and the intracellular calcium content on galvanotaxis indicated that calcium ionic flow from the anode to the cathode within the culture medium permeated the cells through SOCs at the drift velocity, promoting migration toward the cathode. The RTK-PI3K pathway was involved in this process, but the ROCK and MAPK pathways were not. PC3 cells and mouse fibroblasts utilized the same mechanism of galvanotaxis. Together, these results indicated that the signaling pathway responsible for cathode-directed cellular galvanotaxis involved calcium ionic flow from the anode to the cathode within the culture medium, which permeated the cells through SOCs, causing cytoskeletal reorganization via PI3K signaling.

DNA methylation inhibitor, decitabine, promotes MGC803 gastric cancer cell migration and invasion via the upregulation of NEDD4­1.

Gastric cancer is the fourth most common cancer type and the second leading cause of cancer­associated mortality worldwide. Metastasis is a crucial feature of its progression. DNA methylation provides a key epigenetic signature in the epigenetic regulation pathway, and is implicated in transcriptional regulation. CpG sites, which are associated with gene transcriptional activity, are underrepresented in the mammalian genome and tend to be clustered within CpG islands (CGIs) located in the vicinity of the transcription start sites of the majority of the protein­coding genes in humans. The DNA methylation inhibitor, decitabine (DAC), has been demonstrated to be active in hematological disorders. The majority of previous studies in cancer cells demonstrated that DAC inhibits cell proliferation and the motility of the cells. However, since demethylation across the entire genome alters the expression of a large number of genes, the effects of DAC in different tumor cell types are difficult to accurately predict. Neural precursor cell­expressed, developmentally downregulated (NEDD)4­1, a member of the NEDD4 family, which belongs to the E3­ubiquitin ligase family, was reported to be highly expressed in a wide range of tumor types, and it activates the phosphoinositide 3­kinase/Akt pathway by degrading phosphatase and tensin homolog. NEDD4­1 promotes the migration and invasion of glioma cells via the ubiquitination and subsequent degradation of cyclic nucleotide­Ras guanine nucleotide exchange factors (CNrasGEFs). In gastric cardia adenocarcinoma, NEDD4­1 acts as an exceptional prognostic biomarker. In the present study, DAC was revealed to promote the invasive properties of MGC803 gastric cancer cells. NEDD4­1 targeted the CNrasGEF­mediated DAC invasion­promoting activity in MGC803 cells, and CGI methylation in neither the NEDD4 promoter nor the first intron was demonstrated to be associated with this effect. The results of the present study revealed that DAC exerts variable effects in different gastric cancer cell lines and may provide a reference for DAC administration in the clinic.

OCT4B modulates OCT4A expression as ceRNA in tumor cells.

OCT4 is an essential transcription factor for maintaining the self-renewal and the pluripotency of embryonic stem cells (ESCs). The human OCT4 gene can generate three mRNA isoforms (OCT4A, OCT4B and OCT4B1) by alternative splicing. OCT4A protein is a transcription factor for the stemness of ESCs, while the function of OCT4B isoforms remains unclear. Most types of cancer express a relatively low level of OCT4 protein, particularly the OCT4B isoforms. In the present study, we found that OCT4A and OCT4B mRNA were co-expressed in several types of tumor cell lines and tumor samples, and we demonstrated that OCT4B functioned as a non-coding RNA, modulating OCT4A expression in an miRNA-dependent manner [competing endogenous RNA (ceRNA) regulation] at the post-transcription level in the tumor cell lines. This is the first time that ceRNA regulation was observed among spliced isoforms of one gene, and may pave the way for identification of new targets for cancer treatment.

MicroRNA-124 regulates TGF-α-induced epithelial-mesenchymal transition in human prostate cancer cells.

Transforming growth factor-α (TGF-α) is upregulated in advanced stages of prostate cancer and strongly correlated with metastasis. However, the effect of TGF-α on epithelial-mesenchymal transition (EMT) in prostate cancer and the underlying mechanisms remain unclear. Recently, microRNAs have emerged as new regulators of EMT. This study found that treatment of DU145 cells with TGF-α suppressed the expression of epithelial marker E-cadherin and increased the expression of mesenchymal marker Vimentin as well as changed the cell morphology from cobblestone shape to spindle shape. The level of miR-124 was downregulated by TGF-α in several different cancer cell lines. Enforced expression of miR-124 abolished TGF-α-induced EMT. Slug was proven to be a target of miR-124 and mediated the inhibitory effect of miR-124 on TGF-α-induced EMT. Furthermore, overexpression of miR-124 reduced the migratory and invasive capacity of TGF-α-treated DU145 cells. In conclusion, our findings suggest that miR-124 inhibits TGF-α-induced EMT in DU145 cells by targeting Slug. Thus, miR-124 may be a potential target for prostate cancer therapeutic intervention.

ETV1 induces epithelial to mesenchymal transition in human gastric cancer cells through the upregulation of Snail expression.

The ETS family of transcription factors is involved in several physiological and pathological processes including tumor progression. The ETS transcription factors are divided into subfamilies based on the sequence and location of the ETS domain. ETV1 (Ets variant gene 1; also known as ER81), is a member of the PEA3 subfamily, which has been found to promote metastatic progression in several types of human cancer. Previous findings demonstrated that ETV1 expression is upregulated in gastric adenocarcinomas; however, the underlying mechanisms of ETV1-induced metastatic progression in gastric cancer remain elusive. In the present study, we found that the overexpression of ETV1 in normal gastric epithelial cells resulted in epithelial to mesenchymal transition (EMT) and increased invasiveness. Conversely, knockdown of ETV1 resulted in decreased aggressiveness of the invasive gastric cancer cells. Mechanistically, ETV1 transcriptionally upregulates Snail expression. Of note, ETV1 expression is significantly correlated with Snail expression in human gastric tumor samples. In summary, we present data that ETV1 promotes Snail expression to induce EMT-like metastatic progression in gastric cancer.

Hypoxia increases CX3CR1 expression via HIF-1 and NF­κB in androgen-independent prostate cancer cells.

The unique CX3C chemokine CX3CL1 and its cognate receptor CX3CR1 have been implicated in organ-specific metastasis of various types of tumors. Hypoxia, a common phenomenon in solid tumors, is associated with a malignant cancer phenotype. Previous studies have proved that hypoxia facilitates cancer cell metastasis through upregulation of specific chemokine receptors. We hypothesized that hypoxia could upregulate CX3CR1 expression and lead to an increased chemotactic response to CX3CL1 in prostate cancer cells. In the present study, we found that CX3CR1 expression was significantly increased in androgen-independent prostate cancer cells, including DU145, PC-3 and PC-3M, following exposure to hypoxia. This upregulation of CX3CR1 corresponded to a significant increase in migration and invasion of prostate cancer cells under hypoxic conditions, which was attenuated after knocking down CX3CR1 expression. In addition, we examined the possible role of HIF-1 and NF-κB in the process of hypoxia-induced CX3CR1 expression and hypoxia-mediated metastasis. Attenuation of HIF-1 and NF-κB transcriptional activity by siRNAs or pharmacological inhibitors, abrogated hypoxia-induced upregulation of CX3CR1, and also prevented the migration and invasion of DU145 cells under a hypoxic environment. In summary, our study demonstrated that HIF-1 and NF-κB are essential for hypoxia-regulated CX3CR1 expression, which is associated with increased migratory and invasive potential of prostate cancer cells. CX3CR1 signaling is a potential therapeutic target in the adjuvant treatment of prostate cancer.