WTAP-induced N6-methyladenosine of PD-L1 blocked T-cell-mediated antitumor activity under hypoxia in colorectal cancer.

N6-Methyladenosine (m6A) is a important process regulating gene expression post-transcriptionally. Programmed death ligand 1 (PD-L1) is a major immune inhibitive checkpoint that facilitates immune evasion and is expressed in tumor cells. In this research we discovered that Wilms' tumor 1-associated protein (WTAP) degradation caused by ubiquitin-mediated cleavage in cancer cells (colorectal cancer, CRC) under hypoxia was inhibited by Pumilio homolog 1 (PUM1) directly bound to WTAP. WTAP enhanced PD-L1 expression in a way that was m6A-dependent. m6A "reader," Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) identified methylated PD-L1 transcripts and subsequently fixed its mRNA. Additionally, we found that T-cell proliferation and its cancer cell-killing effects were prevented by overexpression of WTAP in vitro and in vivo. Overexpression prevented T cells from proliferating and killing CRC by maintaining the expression of PD-L1. Further evidence supporting the WTAP-PD-L1 regulatory axis was found in human CRC and organoid tissues. Tumors with high WTAP levels appeared more responsive to anti-PD1 immunotherapy, when analyzing samples from patients undergoing treatment. Overall, our findings demonstrated a novel PD-L1 regulatory mechanism by WTAP-induced mRNA epigenetic regulation and the possible application of targeting WTAP as immunotherapy for tumor hypoxia.

Low CPEB1 levels may predict the benefit of 5-fluorouracil treatment in patients with colon or stomach adenocarcinoma.

Background: For patients with colon or stomach adenocarcinoma, 5-fluorouracil (5-FU) is an essential component of systemic chemotherapy in the palliative and adjuvant settings. The post-transcriptional regulatory factor cytoplasmic polyadenylation element-binding protein 1 (CPEB1) has been reported to be linked to tumor metastasis. This study aimed to investigate the relationship between CPEB1 expression and 5-FU treatment response in patients with colon and stomach adenocarcinomas. Methods: The expression of CPEB1 in stomach adenocarcinoma and colorectal cancer (CRC) tissues and in cell lines was determined by quantitative real-time PCR (qRT-PCR) and immunohistochemistry analyses. Transwell assays were employed to analyze the effects of CPEB1 on the migration and invasion abilities of gastric cancer (GC) and CRC cells. Results: The expression levels of CPEB1 were increased in colon and stomach adenocarcinoma and were negatively correlated with malignancy and poor patient survival. Data suggested that patients with CRC or GC who had strong CPEB1 expression responded poorly to 5-FU treatment. Furthermore, knockdown of CPEB1 inhibited the migration and invasion of CRC and GC cells via a mechanism involving decreased expression of matrix metalloprotein (MMP)2, 7, and 9. Finally, our methylated RNA immunoprecipitation PCR (meRIP qPCR) data suggested that the increased CPEB1 expression in colon and stomach adenocarcinomas might be mediated by FTO (FTO alpha-ketoglutarate dependent dioxygenase)-dependent m6A demethylation of CPEB1 mRNA. Conclusions: Our results indicate that the level of CPEB1 expression may be valuable for predicting the benefit of 5-FU treatment for patients with colon and stomach adenocarcinomas. We therefore propose that low CPEB1 expression may represent a novel biomarker for personalized 5-FU therapy.

UBE2C promotes the progression of pancreatic cancer and glycolytic activity via EGFR stabilization-mediated PI3K-Akt pathway activation.

Background: Pancreatic cancer (PC) is among the most prevalent and deadliest endocrine tumors, yet the mechanisms governing its pathogenesis remain to be fully clarified. While ubiquitin-conjugating enzyme E2C (UBE2C) has been identified as an important oncogene in several cancers, its importance in PC has yet to be established. Methods: UBE2C expression in PC tumor samples and cell lines was examined via quantitative real-time polymerase chain reaction (qRT-PCR), while appropriate commercial kits were used to assess lactate production, ATP generation, and the uptake of glucose. Results: UBE2C was found to be upregulated in PC patient tumors and correlated with poorer survival outcomes. In PC cell lines, the silencing of this gene suppressed the malignant activity of cells, thus supporting its identification as an oncogene in this cancer type. Mechanistically, UBE2C was found to promote enhanced matrix metalloproteinase (MMP) protein expression via activating the PI3K-Akt pathway. Moreover, it was found to bind to the epidermal growth factor receptor (EGFR), stabilizing it and driving additional PI3K-Akt pathway activation. UBE2C knockdown in PC cells impaired their uptake of glucose and their ability to produce lactate and ATP. Conclusions: In conclusion, the results of this study support a role for UBE2C as a driver of metastatic PC progression owing to its ability to bind to EGFR and to induce signaling via the PI3K-Akt pathway.

Increased m6A modification of lncRNA DBH-AS1 suppresses pancreatic cancer growth and gemcitabine resistance via the miR-3163/USP44 axis.

Background: Gemcitabine is among the most commonly utilized chemotherapeutic agents for treating pancreatic cancer (PC), yet patients ultimately develop chemoresistance and thus exhibit a poor prognosis. Long noncoding RNAs (lncRNAs) can function as key regulators of PC progression and may serve as prognostic biomarkers in individuals with gemcitabine-resistant PC. This study sought to explore the role of the lncRNA DBH-AS1 in this oncogenic setting. Methods: Based on public databases and qRT-PCR analyses the expression of lncRNA DBH-AS1 in PC tissues and cell lines. The effects of lncRNA DBH-AS1 on proliferation and gemcitabine resistance were determined by in vitro and in vivo experiments. Luciferase reporter assay and RNA immunoprecipitation (RIP) were carried out to reveal the interaction between lncRNA DBH-AS1, miR-3163 and USP44. Results: We found that PC tissues exhibited DBH-AS1 downregulation that was particularly pronounced in gemcitabine-resistant PC tissues and cells. This DBH-AS1 downregulation was negatively correlated with the malignancy of PC tumors and with patient survival outcomes. Additionally, decreased DBH-AS1 expression in PC was found to be linked to the METTL3-dependent m6A methylation of the lncRNA, with functional analyses revealing that DBH-AS1 was able to suppress the growth of PC cells. Mechanistically, DBH-AS1 was able to increase PC cell sensitivity to gemcitabine by sequestering miR-3163 and thus upregulating USP44 in these tumor cells. Clinically, patient-derived PC tumor xenografts exhibiting high levels of DBH-AS1 expression were found to be responsive to gemcitabine treatment. Conclusions: Overall, these data underscore a key role for DBH-AS1 as a regulator of PC tumor growth and a promising therapeutic target capable of predicting PC patient responsiveness to gemcitabine treatment.

Modification of STIM2 by m6A RNA methylation inhibits metastasis of cholangiocarcinoma.

Background: N6-methyladenosine (m6A) is the most frequent internal methylation of eukaryotic RNA (ribonucleic acid) transcripts and plays an important function in RNA processing. The current research aimed to investigate the role of m6A-STIM2 axis in cholangiocarcinoma (CCA) progression. Methods: The expression of STIM2 (Stromal Interaction Molecule 2) in CCA was measured using quantitative polymerase chain reaction (PCR) and immunohistochemistry (IHC). STIM2 was examined in vivo for its effects on the malignant phenotypes of CCA cells. The m6A modification of STIM2 was assessed through MeRIP (methylated RNA Immunoprecipitation)-PCR. Results: Based on the GEPIA (Gene Expression Profiling Interactive Analysis) 2 database findings, a low STIM2 mRNA (messenger RNA) level was related to a poor prognosis in individuals with CCA. Quantitative PCR and IHC assays indicated decreased protein satin in CCA tissues and were associated with extrahepatic metastasis. Vianude mice tail vein injection model indicated that increased STIM2 levels suppressed CCA cell metastasis in vivo, while KRT8 (keratin 8) was detected as the direct downstream target of STIM2-mediated CCA cell metastasis in vivo. Meanwhile, based on SRAMP database and MeRIP assays indicated that m6A alteration resulted in abnormal STIM2 expression in CCA via METTL14 and YTHDC2. Conclusions: Our findings revealed the epi-transcriptomic dysregulation in CCA and metastasis by proposing a complicated STIM2-KRT8 regulatory paradigm based on m6A alteration.

Circular RNA circ_0008934 promotes hepatocellular carcinoma growth and metastasis through modulating miR-1305/TMTC3 axis.

Circular RNAs (circRNAs) play important roles in the progression of hepatocellular carcinoma (HCC). However, the exact function of circ_0008934 in HCC is unknown. Our study aimed to investigate the expression characteristics of circ_0008934 in HCC and its effects on the proliferation and metastasis of HCC, and to explore the potential mechanism. In this study, circ_0008934 expression was found to be significantly upregulated in HCC tissues and cell lines by qRT-PCR. High level of circ_0008934 is closely associated with higher serum AFP (P < 0.001), larger tumor diameter (P = 0.012), microvascular invasion (P = 0.008) and poorer prognosis (P = 0.007) of HCC patients. Functionally, knockdown of circ_0008934 inhibited HCC cell proliferation, invasion and migration in vitro and vivo. Mechanically, circ_0008934 was a sponge of miR-1305 to facilitate the TMTC3 expression, and the TMTC3 expression in HCC tissues was negatively associated with the survival of HCC patients. Furthermore, rescued assays revealed that the circ_0008934 facilitated HCC proliferation, invasion and migration by regulating miR-1305/ TMTC3 signaling pathways. Overall, these results demonstrate that downregulation of circ_0008934 repress HCC growth and metastasis by upregulating miR-1305 to inhibit TMTC3, suggesting circ_0008934/ miR-1305/ TMTC3 regulatory axis may be a possible novel therapeutic target for HCC.

Proteomics Analyses Reveal Functional Differences between Exosomes of Mesenchymal Stem Cells Derived from The Umbilical Cord and Those Derived from The Adipose Tissue.

OBJECTIVE: We aimed to identify the differentially expressed proteins (DEPs) and functional differences between exosomes derived from mesenchymal stem cells (MSCs) derived from umbilical cord (UC) or adipose tissue (AD). MATERIALS AND METHODS: In this experimental study, the UC and AD were isolated from healthy volunteers. Then, exosomes from UC-MSCs and AD-MSCs were isolated and characterized. Next, the protein compositions of the exosomes were examined via liquid chromatography tandem mass spectrometry (LC-MS/MS), followed by evaluation of the DEPs between UC-MSC and AD-MSC-derived exosomes. Finally, functional enrichment analysis was performed. RESULTS: One hundred and ninety-eight key DEPs were identified, among which, albumin (ALB), alpha-II-spectrin (SPTAN1), and Ras-related C3 botulinum toxin substrate 2 (RAC2) were the three hub proteins present at the highest levels in the protein-protein interaction network that was generated based on the shared DEPs. The DEPs were mainly enriched in gene ontology (GO) items associated with immunity, complement activation, and protein activation cascade regulation corresponding to 24 pathways, of which complement and coagulation cascades as well as platelet activation pathways were the most significant. CONCLUSION: The different functions of AD- and UC-MSC exosomes in clinical applications may be related to the differences in their immunomodulatory activities.

Targeted theranostics of lung cancer: PD-L1-guided delivery of gold nanoprisms with chlorin e6 for enhanced imaging and photothermal/photodynamic therapy.

Peptide modified nanoparticles have emerged as powerful tools for enhanced cancer diagnosis and novel treatment strategies. Here, human programmed death-ligand 1 (PD-L1) peptides were used for the first time for the modification of gold nanoprisms (GNPs) to enhance targeting efficiency. A multifunctional nanoprobe was developed that the GNPs@PEG/Ce6-PD-L1 peptide (GNPs@PEG/Ce6-P) was used for imaging-guided photothermal/photodynamic therapy by using the targeting effect of PD-L1. Both confocal imaging and flow cytometry experiments demonstrated a remarkable affinity of the as-prepared nanoprobes GNPs@PEG/Ce6-P to lung cancer cells (HCC827), which have a high PD-L1 expression. Subsequent in vitro and in vivo experiments further demonstrated that the nanoprobes GNPs@PEG/Ce6-P not only allowed for real-time visualization via fluorescence (FL) imaging and photoacoustic (PA) imaging, but also served as phototherapy agents for synergistic photothermal therapy (PTT) and photodynamic therapy (PDT). Furthermore, treatments on human lung cancer cells-derived tumors demonstrated that the nanoprobes GNPs@PEG/Ce6-P could significantly suppress tumor growth through PTT and PDT from GNPs and Ce6, respectively. In conclusion, the as-prepared new nanoprobes show promising potential for nanomedicine with remarkable targeting ability for dual-mode imaging and enhanced PDT and PTT effects on lung cancer.

Circular RNAs in gastric cancer: Biomarkers for early diagnosis.

Circular RNAs (circRNAs) are highly conserved and stable closed-loop non-coding RNAs. They are involved in numerous biological functions, including regulating gene transcription or protein translation by interacting with proteins and regulating expression of microRNAs. The aberrant expression of circRNAs has been reported in many cancers, including gastric cancer. By regulating gene expression, circRNAs are able to affect the proliferation, invasion and metastasis of gastric cancer. The current review focused on the characteristics and biological functions of circRNAs, the carcinogenic potential and the possible implications of circRNAs on the diagnosis and treatment of gastric cancer. In conclusion, circRNAs may serve as potential biomarkers for diagnosis, as well as therapeutic targets.

Hsa_circ_0003998 promotes epithelial to mesenchymal transition of hepatocellular carcinoma by sponging miR-143-3p and PCBP1.

BACKGROUND: Circular RNAs (circRNAs) play a critical regulatory role in cancer progression. However, the underlying mechanisms of circRNAs in hepatocellular carcinoma (HCC) metastasis remain mostly unknown. METHODS: Has_circ_0003998 (circ0003998) was identified by RNAs sequencing in HCC patients with /without portal vein tumor thrombus (PVTT) metastasis. The expression level of circ0003998 was further detected by in situ hybridization on tissues microarray (ISH-TMA) and qRT-PCR in 25 HCC patients with PVTT metastasis. Moreover, the 25 HCC patients with PVTT metastasis and 50 HCC patients without PVTT metastasis were recruited together to analyze the correlation between circ0003998 expression and HCC clinical characteristics. Transwell, migration and CCK8 assays, as well as nude mice model of lung or liver metastasis were used to evaluate the role of circ0003998 in epithelial to mesenchymal transition (EMT) in HCC. The regulatory mechanisms of circ0003998 in miR-143-3p and PCBP1 were determined by dual-luciferase reporter assay, nuclear-cytoplasmic fractionation, fluorescent in situ hybridization, RNA pull- down, microRNA sequence, western blot and RNA immunoprecipitation. RESULTS: Compared with adjacent normal liver tissues (ANL), circ0003998 expression was significantly upregulated in PVTT tissues and HCC tissues, and its expression correlates with the aggressive characteristics of HCC patients. Further assays suggested that circ0003998 promoted EMT of HCC both in vitro and in vivo. Mechanistically, our data indicated that circ0003998 may act as a ceRNA (competing endogenous RNA) of microRNA-143-3p to relieve the repressive effect on EMT-related stimulator, FOSL2; meanwhile, circ0003998 could bind with PCBP1-poly(rC) binding protein 1 (PCBP1) to increase the expression level of EMT-related genes, CD44v6. CONCLUSION: Circ0003998 promotes EMT of HCC by circ0003998/miR-143-3p/FOSL2 axis and circ0003998 /PCBP1/CD44v6 axis.

Effects of gold nanoprism-assisted human PD-L1 siRNA on both gene down-regulation and photothermal therapy on lung cancer.

Gold nanoprisms (GNPs) have been broadly studied for the potential applications in both imaging and treatment on tumors due to their special characteristics. Herein we reported that a new nanoplatform GNPs@PSS/PDADMAC-siRNA (GNPs-siRNA) was designed and fabricated by sequentially coating the GNPs with poly (sodium 4-styrenesulfonate) (PSS) and poly (-diallyldimethylammonium chloride) (PDADMAC) to carry small interfering RNA (siRNA). Human program death-ligand 1 (PD-L1) was recently known to be crucial for cancer cell survival through the intrinsic signaling activities, besides serving as an important checkpoint gene in immune system. We successfully attached the human PD-L1 siRNA to the surface of GNPs@PSS/PDADMAC to obtain the GNPs-hPD-L1 siRNA nanoplatform. Real Time Cellular Analysis (RTCA) assay demonstrated that GNPs-hPD-L1 siRNA exhibited remarkable capacity to inhibit the proliferation of human lung cancer cells. Subsequent in vitro and in vivo experiments verified that the GNPs-hPD-L1 siRNA not only functioned as a carrier for siRNA delivery to down-regulate the hPD-L1 expression, but also served for photoacoustic (PA) imaging and photothermal agents for photothermal therapy (PTT) in both human lung cancer cells and human lung cancer cells-derived tumors. Our findings could be expected to provide an innovative direction for future clinical transformation application. STATEMENT OF SIGNIFICANCE: To our knowledge, this is the first paper related to the hPD-L1 siRNA delivery combined with the gold nanoparticles, especially the gold nanoprisms. The as-prepared GNPs-hPD-L1 siRNA nanoplatform not only functioned as a carrier for siRNA delivery to down-regulate the PD-L1 expression, but also acted as photothermal agents for theranostic effects in both human lung cancer cells and human lung cancer cells-derived tumors. The as-prepared GNPs-hPD-L1 siRNA nanoplatform could knock down human PD-L1 gene expression, which caused the inhibition on proliferation of human lung cancer cell in vitro or in vivo. The as-prepared GNPs-hPD-L1 siRNA nanoplatform possessed excellent photoacoustic imaging ability and photothermal therapy effects.

Hsa_circ_0003998 may be used as a new biomarker for the diagnosis and prognosis of hepatocellular carcinoma.

BACKGROUND: Circular RNAs (circRNAs) play important roles in the progression of cancers, but the precise role of circRNAs in the diagnosis and prognosis of hepatocellular carcinoma (HCC) remains to be clarified. The aim of the current study was to explore the diagnostic and prognostic values of hsa_circ_0003998 in HCC. METHODS: CircRNAs expression was measured using RNA-seq analysis from HCC tissues (n=6) (three cases with or without portal vein invasion). Hsa_circ_0003998 in 200 pairs of HCC and adjacent noncancerous tissues and HCC cell lines was examined using qRT-PCR and the clinicopathologic significance was determined. We also detected the plasma levels of hsa_circ_0003998 in HCC, hepatitis B patients and healthy controls. The clinical diagnosis and prognostic values were further determined using receiver operating characteristic (ROC) curve, Kaplan-Meier curve and Cox regression. RESULTS: Hsa_circ_0003998 was upregulated in HCC tissues (P<0.001) and HCC cell lines (HepG2, HuH7, MHCC97H) (P<0.001). In addition, upregulation of hsa_circ_0003998 level was associated with higher serum alpha-fetoprotien (AFP) level (P=0.003), larger tumor diameter (P=0.009), lower differentiation level (P=0.023) and microvascular invasion (P=0.028). The plasma level of hsa_circ_0003998 in HCC patients was significantly higher than those in hepatitis B patients (P<0.001) and healthy controls (P<0.001). Its level was significantly reduced after the operation (P<0.001). The area under the ROC curve (AUC) for distinguishing HCC from adjacent noncancerous tissues was 0.894 (95% CI=0.86-0.922, P<0.001), the sensitivity and specificity were 0.84 and 0.8, respectively. Comparing with hepatitis B patients and healthy controls, hsa_circ_0003998, respectively, had an AUC value of 0.833 (95% CI=0.763-0.889, P<0.001) and 0.892 (95% CI=0.831-0.937, P<0.001). Their sensitivity and specificity were 0.83, 0.7 and 0.8, 0.84, respectively. Moreover, the combination of hsa_circ_0003998 and AFP showed the highest AUC value of 0.947, the sensitivity and specificity were 0.88 and 0.92, respectively. The hsa_circ_0003998 (P=0.003) and AFP (P=0.008) levels were independent prognostic factors for HCC. The overall survival of HCC patients with high level of hsa_circ_0003998 was significantly poorer than those with low level (P=0.005). CONCLUSION: Our findings suggest that hsa_circ_0003998 may be used as a novel potential biomarker for the diagnosis and prognosis of HCC patients.

Dual-modified cationic liposomes loaded with paclitaxel and survivin siRNA for targeted imaging and therapy of cancer stem cells in brain glioma.

Development of safe, efficient nanocomplex for targeted imaging and therapy of cancer stem cells in brain glioma has become a great challenge. Herein, a low-density lipoprotein receptor-related protein and a RNA aptamer bound CD133 were used as dual-targeting ligands to prepare dual-modified cationic liposomes (DP-CLPs) loaded with survivin siRNA and paclitaxel (DP-CLPs-PTX-siRNA) for actively targeting imaging and treating CD133+ glioma stem cells after passing through the blood-brain barrier. After being administrated with DP-CLPs-PTX-siRNA nanocomplex, DP-CLPs showed a persistent target ability to bind glioma cells and brain microvascular endothelial cells (BCECs) and to deliver drugs (PTX/siRNA) to CD133+ glioma stem cells. Prepared DP-CLPs-PTX-siRNA nanocomplex showed very low cytotoxicity to BCECs, but induced selectively apoptosis of CD133+ glioma stem cells, and improved CD133+ glioma stem cells' differentiation into non-stem-cell lineages, also markedly inhibited tumorigenesis, induced CD133+ glioma cell apoptosis in intracranial glioma tumor-bearing nude mice and improved survival rates. In conclusion, prepared DP-CLPs-PTX-siRNA nanocomplex selectively induced CD133+ glioma stem cell apoptosis in vitro and in vivo exhibits great potential for targeted imaging and therapy of brain glioma stem cells.

Prognostic value of CD44v6 expression in breast cancer: a meta-analysis.

PURPOSE: The prognostic value and clinical significance of CD44 variant isoform v6 (CD44v6) in breast cancer remains controversial. Our study aimed to generalize the correlation between CD44v6 expression and clinicopathological features and prognosis in breast cancer by using a meta-analysis. METHODS: We performed a comprehensive search of relevant literature from PubMed, Cochrane Database, and EMBASE database that were published before January 2018. The pooled ORs and HRs with 95% CIs were used to estimate the effects. RESULTS: Thirteen articles comprising 1,458 patients were included for analysis. The results revealed that CD44v6 expression was associated with histological grade (overall: OR=1.56, 95% CI [1.06, 2.29], P=0.023; Asian: OR=1.78, 95% CI [1.12, 2.85], P=0.016) and lymph node metastasis (overall: OR=1.96, 95% CI [1.01, 3.78], P=0.046; Asian: OR=2.11, 95% CI [1.00, 4.44], P=0.049). CD44v6 expression was significantly associated with poor prognosis in patients with breast cancer (overall survival: overall: HR=1.55, 95% CI [1.09, 2.22], P=0.015; Asian: HR=2.22, 95% CI [1.34, 3.68], P=0.002). CONCLUSION: Our meta-analysis demonstrates that CD44v6 is significantly associated with poor prognosis, histological grade, and lymph node metastasis in breast cancer patients, especially among Asian patients.

Role of non-coding RNAs in cardiotoxicity of chemotherapy.

The long-time paradoxical situation of non-coding RNAs (ncRNAs) has been terminated for they emerge as executive at full spectrum of gene expression and translation. More recently, it has been demonstrated that some ncRNAs apparently are associated with chemotherapy, causing cardiotoxicity, which taint long-term recovery of patients in growing body of evidence. The current review focused on up-to-date knowledge on regulation change and molecular signaling of ncRNAs, at mean time evaluate their potentials as diagnostic biomarkers or therapeutic targets to monitor and protect cardio function.

miR-598 inhibits metastasis in colorectal cancer by suppressing JAG1/Notch2 pathway stimulating EMT.

MicroRNAs (miRNAs) are a class of endogenous, evolutionarily conserved small non-coding RNA molecules that mediate the posttranscriptional process of target gene, leading to translational repression or degradation of target mRNAs. A series of studies have indicated that miRNAs play an important role in tumor initiation, development and progression. In this study, we found that down regulation of miR-598 was a frequent event in CRC tissues compared to the paracarcinoma tissues. And the study demonstrated that miR-598 was implicated in CRC metastasis. Transwell migration assay revealed that elevated miR-598 expression reduces CRC cell migration. Moreover, our study showed that suppression of miR-598 expression induces CRC cell epithelialmesenchymal transition(EMT) and overexpression of miR-598 inhibits CRC cell EMT. In addition, bioinformatics target prediction identified JAG1 as a putative target of miR-598. Knockdown of miR-598 was shown to upregulate JAG1 expression. Furthermore, overexpression of miR-598 suppressed the expression of JAG1. Consistent results were also obtained when the regulation of JAG1 expression by miR-598 was further specified in CRC tissues. Moreover, overexpression of JAG1 induces epithelialmesenchymal transition(EMT) and promotes the metastasis of CRC cells. Decreased Notch2 expression suppresses CRC cells metastasis and EMT. Together, these results indicate that miR-598 is a novel regulator of colorectal cancer metastasis. Our data suggest miR-598 is implicated in regulating Epithelial-mesenchymal transitions by directly suppressing its downstream target gene JAG1 to inactivate Notch signaling pathway.

CBX6 overexpression contributes to tumor progression and is predictive of a poor prognosis in hepatocellular carcinoma.

Aberrant chromobox (CBX) family protein expression has been reported in a variety of human malignancies. However, the role of CBX6 in hepatocellular carcinoma (HCC) progression and patient prognosis remains unknown. In this study, we found that CBX6 was frequently up-regulated in HCC clinical samples and HCC cell lines and that CBX6 expression was significantly correlated with larger tumor sizes (≥ 5 cm, p = 0.011) and multiple tumors (n ≥ 2, p = 0.018). Survival analyses indicated that patients with higher CBX6 expression levels had significantly shorter recurrence-free survival (RFS) and overall survival (OS) than patients with lower CBX6 expression levels, and multivariate analyses confirmed that increased CBX6 expression was an independent unfavorable prognostic factor for HCC patients. Functional study demonstrated that CBX6 profoundly promoted HCC cell growth both in vitro and in vivo, and mechanistic investigation revealed that the S100A9/NF-κB/MAPK pathway was essential for mediating CBX6 function. In conclusion, our results represent the first evidence that CBX6 contributes to tumor progression and indicate that the protein may serve as a novel prognostic biomarker for HCC and as a therapeutic target in the treatment of the disease.

Prognostic significance of circulating tumor cells in esophageal carcinoma: a meta-analysis.

PURPOSE: The prognostic significance of circulating tumor cells (CTCs) in esophageal carcinoma (EC) is controversial. We aim to assess its association with clinicopathological and prognostic relevance in EC by using a meta-analysis. METHODS: We searched PubMed, Cochrane Database, Embase databases, and the references in relevant studies that assessed the clinicopathological or prognostic relevance of CTCs in peripheral blood of patients with EC. Statistical analyses were conducted by using Stata software to calculate the pooled odds ratio (OR), hazard ratio (HR), and 95% confidence intervals (CIs) using fixed or random-effects models according to the heterogeneity of included studies. The subgroup analyses were performed according to ethnicity, histological type, and detection method. RESULTS: Sixteen trials containing 1,260 patients were included for analysis. Pooled results showed that presence of CTCs was significantly associated with poor overall survival (HR =1.71, 95% CI [1.30, 2.12], P<0.001) and progression-free survival (HR =1.67, 95% CI [1.19, 2.15], P<0.001) in EC patients. Subgroup analysis indicated that presence of CTCs was closely associated with worse overall survival (Asian: HR =1.66, 95% CI [1.24, 2.08], P<0.001; squamous cell carcinoma [SCC]: HR =1.66, 95% CI [1.24, 2.08], P<0.001; no polymerase chain reaction [PCR]: HR =2.08, 95% CI [1.40, 2.76], P<0.001) and progression-free survival (Asian: HR =1.63, 95% CI [1.15, 2.12], P<0.001; SCC: HR =1.63, 95% CI [1.15, 2.12], P<0.001; PCR: HR =1.63, 95% CI [1.15, 2.12], P<0.001). Additionally, ORs showed that presence of CTCs was significantly correlated with tumor node metastasis (TNM) staging (overall: OR = 1.96, 95% CI [1.34, 2.87], P=0.001; Asian: OR =2.09, 95% CI [1.37, 3.19], P=0.001; SCC: OR =1.97, 95% CI [1.21, 3.07], P=0.003; PCR: OR =2.23, 95% CI [1.43, 3.47], P<0.001), venous invasion (overall: OR =2.23, 95% CI [1.46, 3.40], P<0.001; Asian: OR =2.23, 95% CI [1.46, 3.40], P<0.001; SCC: OR =2.23, 95% CI [1.46, 3.40], P<0.001; PCR: OR =2.23, 95% CI [1.46, 3.40], P<0.001), lymph node metastasis (overall: OR =2.41, 95% CI [1.50, 3.86], P<0.001; Asian: OR =2.89, 95% CI [1.80, 4.65], P<0.001; SCC: OR =2.44, 95% CI [1.47, 4.07], P=0.001; PCR: OR =2.89, 95% CI [1.80, 4.65], P<0.001) and distant metastasis (Asian: OR =2.68, 95% CI [1.01, 7.08], P=0.047) in patients with EC. CONCLUSION: The presence of CTCs indicates a poor prognosis in EC patients, especially in Asian and SCC patients. Further well-designed prospective studies are recommended to explore the clinical applications of CTCs in patients with EC.

Heterogeneous expression and biological function of ubiquitin carboxy-terminal hydrolase-L1 in osteosarcoma.

Ubiquitin carboxyl terminal hydrolase 1 (UCHL1), a member of the UCH class of DUBs, has been reported as either an oncogene or a tumor suppressor. However, the molecular mechanism underlying the biological function of UCHL1 in osteosarcoma is still unclear. This study was aimed at elucidating the roles of UCHL1 in regulating the biological behavior of osteosarcoma cells. In this study, we found that UCHL1 was elevated in osteosarcoma compared with normal bone tissue. Moreover, UCHL1 expression level was correlated with tumor maximum diameter, high rate of lung metastases and short survival time. Then, we found that knockdown of UCHL1 in osteosarcoma cell MG63 inhibited cell proliferation and significantly increased cell population in the G1 phase. Several cyclins promoting G1/S phase transition were reduced after UCHL1 knockdown, including cell cycle regulator cyclin D1, cyclin E1 and CDK6. Moreover, inhibition of UCHL1 in MG63 cells dramatically induced cell apoptosis. We also found that down-regulation of UCHL1 in MG63 significantly inhibited cell invasion. Then, we found that there was a positive correlation between UCHL1 expression level and the Akt and ERK phosphorylation status. Finally, in vivo data showed that knockdown of UCHL1 inhibited osteosarcoma growth in nude mice. These results indicate that UCHL1 could work as an oncogene and may serve as a promising therapeutic strategy for osteosarcoma.

Pirarubicin-based chemotherapy displayed better clinical outcomes and lower toxicity than did doxorubicin-based chemotherapy in the treatment of non-metastatic extremity osteosarcoma.

Pirarubicin (THP) is a newer generation anthracycline anticancer drug with antineoplastic efficacy against numerous tumors. Few studies have reported its application and efficiency in anti-osteosarcoma chemotherapeutic strategies. Ninety-six non-metastatic extremity osteosarcoma patients treated with THP or doxorubicin (DOX) in combination with high-dose methotrexate (HDMTX), cisplatin (DDP) and ifosfamide (IFO) within the past 9 years at our hospital were evaluated retrospectively to compare efficacy and side effects. Among the patients, 55.2% were male, 36.5% were ≤14 years old and 59.4% presented with a large tumor (≥1/3 of bone) to our department. The 5-year disease-free survival (DFS) rate of the patients treated with the THP-based chemotherapeutic regimen was 70.2%, significantly higher than that of the DOX-based regimen-treated group (53.1%). The THP-based chemotherapeutic regimen decreased the lung metastatic rate significantly compared with the DOX-based regimen (19.1% vs. 36.7%, P=0.045), as well as the relapse rate (31.9% vs. 49.0%, P=0.067). Both regimens were generally well tolerated. However, while the THP-based chemotherapeutic regimen did not alter toxicity in the hematologic system, liver or kidneys compared with the DOX-based regimen, it showed lower rates of alopecia (63.8% vs. 85.7%, P=0.012), nausea and vomiting (51.1% vs. 79.6%, P=0.003), and mucositis (48.9% vs. 75.6%, P=0.003). THP also resulted in lower cardiac toxicity. Our data demonstrate that the THP-based regimen is better than the DOX-based regimen in terms of the 5-year DFS rate, pulmonary metastasis rate, relapse rate and side effects.