Increased expression of LINC00323 correlates with tumor progression and poor prognosis of gastric cancer.

BACKGROUD/AIMS: LINC00323 is a novel lncRNA which has reported to play an important role in the development and recurrence in several cancers. However, the expression and predictive value of LINC00323 in gastric cancer (GC) remain mysterious. METHODS: LINC00323 expression in GC tissues and adjacent normal tissues was evaluated by quantitative reverse-transcription PCR (qRT-PCR). The relationship between LINC00323 expression and clinicopathological features and patients' survival were analyzed. Univariate and multivariate survival analyses were performed. RESULTS: LINC00323 expression were found to be significantly increased in GC tissues. High expression of LINC00323 exerted a pro-tumor effect in the late stage of GC development. Kaplan-Meier analysis showed that patients with high LINC00323 were associated with poor overall survival (OS) and progression-free survival (PFS). Moreover, the combination of TNM stage and drinking status better identified GC patient outcome than those of TNM stage alone. CONCLUSIONS: Our data showed that LINC00323 overexpression might serve as a novel independent prognostic factor for survival of GC patients, suggesting LINC00323 was a potential biomarker and therapeutic target for GC.

A somatic mutation-derived LncRNA signatures of genomic instability predicts the prognosis and tumor microenvironment immune characters in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive carcinoma with genome instability. Long non-coding RNAs (LncRNAs) have been functionally associated with genomic instability in cancers. However, the identification and prognostic value of lncRNAs related to genome instability have not been explored in hepatocellular carcinoma. In this study, we aim to identify a genomic instability-related lncRNA signature for predicting prognosis and the efficacy of immunotherapy in HCC patients. METHODS: According to the somatic mutation and transcript data of 364 patients with HCC, we determined differentially expressed genome instability-related lncRNAs (GInLncRNAs). Gene ontology (GO) enrichment analyses and Kyoto Encyclopedia of genes and genomes enrichment analyses revealed the potential functions of genes co-expressed with those lncRNAs involved in cancer development and immune function. We further determined a genome instability-related lncRNA signature (GInLncSig) through Cox regression analysis and LASSO regression analysis. Thereafter, we performed correlation analyses with mutations, clinical stratification analyses, and survival analyses to evaluate GInLncSig predictive function. Subsequently, we construct a nomogram model for prognostic assessments of patients with HCC. Finally, we performed Immunocytes infiltration analysis, gene set enrichment analysis (ssGSEA) of immunity circle-associated pathways, and T cell-inflamed score to explore GInLncSig's potential value in guiding immunotherapy. RESULTS: We identified 11 independent prognosis-associated GInLncRNAs (AC002511.2, LINC00501, LINC02055, LINC02714, LINC01508, LOC105371967, RP11_96A15.1, RP11_305F18.1, RP11_342M1.3, RP11_432J24.3, U95743.1) to construct a GInLncSig. According to the risk score calculated by GInLncSig, the high-risk group was characterized by a higher somatic mutation count, significantly poorer clinical prognosis, higher T cell-inflamed score, and specific tumor immune infiltration status compared to the low-risk group. Furthermore, we constructed a nomogram model to improve the reliability and clinical utility of predicting the prognosis of patients with HCC. CONCLUSION: Our study established a reliable prognostic prediction signature that could be a tool for prognosis prediction and a promising predictive biomarker of immunotherapy in hepatocellular carcinoma.

Construction of a competing endogenous RNA network and identification of potential regulatory axes in gastric cancer chemoresistance.

BACKGROUND: Emerging evidence highlights the multifunctional role of noncoding RNAs (ncRNAs) in gastric cancer (GC) chemoresistance. However, the comprehensive expression profile and competing endogenous RNAs (ceRNAs) regulatory network of GC chemoresistance remain unanswered. METHODS: The whole-transcriptome sequencing (RNA sequencing) was performed to comprehensively analyze the differentially expressed (DE) lncRNAs, miRNAs and mRNAs in cisplatin-resistant cells MGC-803/DDP and GC cells MGC-803. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to investigate the biological functions implicated with the DEncRNAs. Then, the cisplatin-resistant-related ceRNA network and potential regulatory axes were constructed by bioinformatic analysis. RESULTS: We successfully generated cisplatin-resistant GC cell line MGC-803/DDP. Differential expression analysis showed that a total of 1936 DElncRNAs, 2194 DEmRNAs and 174 DEmiRNAs were identified. Functional enrichment analysis indicated that those DEncRNAs were mainly involved in neuroactive ligand-receptor interaction, drug metabolism and Hippo signaling pathway. Subsequently, the cisplatin-resistant-related ceRNA network was constructed with the widely accepted vital chemo-resistant-related genes and signaling pathways. In addition, two constructed regulatory axes (include FAM66C/miR-129-5p/7 mRNAs and SFTA1P/miR-206/FN1 or NRP1) were successfully validated by the Genomic Data Commons (GDC) GC data. CONCLUSIONS: The novel ceRNA network and the potential regulatory axes may provide the most comprehensive view of GC chemoresistance to date. Our findings uncovered potential biomarkers for prognostic prediction and novel therapeutic targets for reversing cisplatin resistance in GC.

High miR-3650 expression in nasopharyngeal carcinoma and its clinical prognostic values.

BACKGROUND: A recent study has reported that miR-3650 expression was significant reduced in hepatocellular carcinoma and predicted poor prognosis. However, the role of miR-3650 in nasopharyngeal carcinoma (NPC) remains indefinite. METHODS: Total 140 cases of NPCs were included in this study. The expression of miR-3650 was determined in NPC tissues and adjacent nontumor tissues using qRT-PCR. Then the relationship between miR-3650 expression and clinicopathological features as well as survival were analyzed. RESULTS: The expression of miR-3650 was significant higher in NPC tissues than that in adjacent nontumor tissues (P < 0.001). High expression of miR-3650 was significant correlated with tumor progression and distant metastasis of NPC patients. And patients with high miR-3650 expression have much worse 5-year overall survival (OS) and 5-year progression-free survival (PFS) than those with low expression (all P < 0.0001). Furthermore, Cox regression analysis showed that miR-3650 was an independent risk predictor for OS and PFS in NPC patients (all P = 0.000). CONCLUSION: Our results demonstrated for the first time that miR-3650 was markedly upregulated in NPC tissues and positively associated with tumor progression and poor survival, suggesting that miR-3650 may be a potential novel prognostic biomarker and therapeutic target for NPC patients.

Rab1A promotes cancer metastasis and radioresistance through activating GSK-3ß/Wnt/ß-catenin signaling in nasopharyngeal carcinoma.

Many articles have reported that Rab1A was overexpressed in a variety of human cancers and involved in tumor progression and metastasis. However, the biological function and molecular mechanism of Rab1A in nasopharyngeal carcinoma (NPC) remained unknown until now. Here we found that Rab1A overexpression is a common event and was positively associated with distant metastasis and poor prognosis of NPC patients. Functionally, Rab1A depletion inhibited the migration and EMT phenotype of NPC cells, whereas Rab1A overexpression led to the opposite effect. Furthermore, we reveal an important role for Rab1A protein in the induction of radioresistance via regulating homologous recombination (HR) signaling pathway. Mechanistically, Rab1A activated Wnt/ß-catenin signaling by inhibiting the activity of GSK-3ß via phosphorylation at Ser9. Then Wnt/ß-catenin signaling induced NPC cells radioresistance and metastasis through nuclear translocation of ß-catenin and transcription upregulation of HR pathway-related and EMT-related genes expression. In general, this study shows that Rab1A may serve as a potential biomarker for predicting prognosis in NPC patients. Targeting Rab1A and Wnt/ß-catenin signaling may hold promise to overcome NPC radioresistance.

The prognostic value of a seven-lncRNA signature in patients with esophageal squamous cell carcinoma: a lncRNA expression analysis.

BACKGROUND: Long non-coding RNAs (lncRNAs) have been reported to be prognostic biomarkers in many types of cancer. We aimed to identify a lncRNA signature that can predict the prognosis in patients with esophageal squamous cell carcinoma (ESCC). METHODS: Using a custom microarray, we retrospectively analyzed lncRNA expression profiles in 141 samples of ESCC and 81 paired non-cancer specimens from Sun Yat-Sen University Cancer Center (Guangzhou, China), which were used as a training cohort to identify a signature associated with clinical outcomes. Then we conducted quantitative RT-PCR in another 103 samples of ESCC from the same cancer center as an independent cohort to verify the signature. RESULTS: Microarray analysis showed that there were 338 lncRNAs significantly differentially expressed between ESCC and non-cancer esophagus tissues in the training cohort. From these differentially expressed lncRNAs, we found 16 lncRNAs associated with overall survival (OS) of ESCC patients using Cox regression analysis. Then a 7-lncRNA signature for predicting survival was identified from the 16 lncRNAs, which classified ESCC patients into high-risk and low-risk groups. Patients with high-risk have shorter OS (HR: 3.555, 95% CI 2.195-5.757, p < 0.001) and disease-free survival (DFS) (HR: 2.537, 95% CI 1.646-3.909, p < 0.001) when compared with patients with low-risk in the training cohort. In the independent cohort, the 7 lncRNAs were detected by qRT-PCR and used to compute risk score for the patients. The result indicates that patients with high risk also have significantly worse OS (HR = 2.662, 95% CI 1.588-4.464, p < 0.001) and DFS (HR 2.389, 95% CI 1.447-3.946, p < 0.001). The univariate and multivariate Cox regression analyses indicate that the signature is an independent factor for predicting survival of patients with ESCC. Combination of the signature and TNM staging was more powerful in predicting OS than TNM staging alone in both the training (AUC: 0.772 vs 0.681, p = 0.002) and independent cohorts (AUC: 0.772 vs 0.660, p = 0.003). CONCLUSIONS: The 7-lncRNA signature is a potential prognostic biomarker in patients with ESCC and may help in treatment decision when combined with the TNM staging system.

Beneficial effects of Cripto-1 for transarterial chemoembolization in hepatocellular carcinoma.

Cripto-1 may act as an independent predictor for prognosis in hepatocellular carcinoma (HCC). However, the function of Cripto-1 in HCC cells and its response to postoperative transarterial chemoembolization (TACE) in HCC patients remains unclearly. Up-regulated Cripto-1 expression boosted the ability of cell proliferation, migration and invasion in HCC cells in vitro. While opposite results were observed in HCC cells with down-regulated Cripto-1 expression. Cripto-1 expression was correlated with epithelial-mesenchymal transition (EMT) relevant biomarkers. Furthermore, in high Cripto-1 expression patients, those with adjuvant TACE had favorable TTR and OS times. On contrary, adjuvant TACE may promote tumor recurrence but had no influence on OS time in patients with low Cripto-1 expression. In different subgroups of vascular invasion, larger tumor size or liver cirrhosis, patients with adjuvant TACE had longer TTR and OS times than those without TACE in patients with high Cripto-1 expression, while they could not obtain benefits from adjuvant TACE in patients with low-expressed Cripto-1 expression. In conclusion, Cripto-1 may be a potential prognostic factor in predicting outcome of HCC patients with TACE therapy, and combined with Cripto-1 and tumor features may be helpful to stratify patients with respect to prognosis and response to adjuvant TACE.

LINC01133 as ceRNA inhibits gastric cancer progression by sponging miR-106a-3p to regulate APC expression and the Wnt/ß-catenin pathway.

BACKGROUND: Gastric cancer (GC) is a common malignancy and frequent cause of cancer-related death. Long non-coding RNAs (lncRNAs) have emerged as important regulators and tissue-specific biomarkers of multiple cancers, including GC. Recent evidence has indicated that the novel lncRNA LINC01133 plays an important role in cancer progression and metastasis. However, its function and molecular mechanism in GC remain largely unknown. METHODS: LINC01133 expression was detected in 200 GC and matched non-cancerous tissues by quantitative reverse transcription PCR. Gain- and loss-of-function experiments were conducted to investigate the biological functions of LINC01133 both in vitro and in vivo. Insights into the underlying mechanisms of competitive endogenous RNAs (ceRNAs) were determined by bioinformatics analysis, dual-luciferase reporter assays, quantitative PCR arrays, TOPFlash/FOPFlash reporter assay, luciferase assay, and rescue experiments. RESULTS: LINC01133 was downregulated in GC tissues and cell lines, and its low expression positively correlated with GC progression and metastasis. Functionally, LINC01133 depletion promoted cell proliferation, migration, and the epithelial-mesenchymal transition (EMT) in GC cells, whereas LINC01133 overexpression resulted in the opposite effects both in vitro and in vivo. Bioinformatics analysis and luciferase assays revealed that miR-106a-3p was a direct target of LINC01133, which functioned as a ceRNA in regulating GC metastasis. Mechanistic analysis demonstrated that miR-106a-3p specifically targeted the adenomatous polyposis coli (APC) gene, and LINC01133/miR-106a-3p suppressed the EMT and metastasis by inactivating the Wnt/ß-catenin pathway in an APC-dependent manner. CONCLUSIONS: Our findings suggest that reduced expression of LINC01133 is associated with aggressive tumor phenotypes and poor patient outcomes in GC. LINC01133 inhibits GC progression and metastasis by acting as a ceRNA for miR-106a-3p to regulate APC expression and the Wnt/ß-catenin pathway, suggesting that LINC01133 may serve as a potential prognostic biomarker and anti-metastatic therapeutic target for GC.

Predictive Value of LINC01133 for Unfavorable Prognosis was Impacted by Alcohol in Esophageal Squamous Cell Carcinoma.

BACKGROUND/AIMS: Considerable evidence indicates that long noncoding RNAs (lncRNAs) exert importantly regulatory functions during human cancer initiation and progression and are promising biotargets in the flight against cancer. METHODS: In this study, we evaluated the role of the lncRNA LINC01133 in esophageal squamous cell carcinoma (ESCC). LINC01133 expression in ESCC was examined by quantitative real-time PCR. The correlations between LINC01133 expression and clinicopathological variables and survival were examined by the χ2 test, Kaplan-Meier method, log-rank test, and univariate Cox regression analysis. RESULTS: LINC01133 expression levels were frequently lower in ESCC tissues and cell lines than in paired normal tissues and an immortalized esophageal epithelial cell line, respectively. The expression of LINC01133 decreased in a TNM stage- and lifestyle-independent manner. LINC01133 was an independent protective factor and had an anti-tumor effect in the early stage of ESCC development. More importantly, we discovered that drinking status in our cohort impaired the predictive accuracy of LINC01133 for patients with ESCC. Furthermore, a new risk model combining LINC01133 expression, drinking status, and TNM stage provided better survival discrimination compared with three other predictors. CONCLUSIONS: Our data indicate that a loss of LINC01133 expression is a potential poor prognostic biomarker and therapeutic target for ESCC and provide additional prognostic information to improve the outcomes of ESCC patients.

Epithelial cell adhesion molecule overexpression regulates epithelial-mesenchymal transition, stemness and metastasis of nasopharyngeal carcinoma cells via the PTEN/AKT/mTOR pathway.

Epithelial cell adhesion molecule (EpCAM) is known to be highly expressed in a variety of epithelial carcinomas, and it is involved in cell adhesion and proliferation. However, its expression profile and biological function in nasopharyngeal carcinoma (NPC) remains unclear. In this study, higher expression of EpCAM was found in NPC samples compared with non-cancer nasopharyngeal mucosa by qRT-PCR. Additionally, immunohistochemistry (IHC) analysis of NPC specimens from 64 cases showed that high EpCAM expression was associated with metastasis and shorter survival. Multivariate survival analysis identified high EpCAM expression as an independent prognostic factor. Ectopic EpCAM expression in NPC cells promoted epithelial-mesenchymal transition (EMT), induced a cancer stem cell (CSC)-like phenotype, and enhanced metastasis in vitro and in vivo without an effect on cell proliferation. Notably, EpCAM overexpression reduced PTEN expression and increased the level of AKT, mTOR, p70S6K and 4EBP1 phosphorylation. Correspondingly, an AKT inhibitor and rapamycin blocked the effect of EpCAM on NPC cell invasion and stem-like phenotypes, and siRNA targeting PTEN rescued the oncogenic activities in EpCAM knockdown NPC cells. Our data demonstrate that EpCAM regulates EMT, stemness and metastasis of NPC cells via the PTEN/AKT/mTOR pathway.

BMP2 promotes proliferation and invasion of nasopharyngeal carcinoma cells via mTORC1 pathway.

Bone morphogenetic protein-2 (BMP2) is a secreted protein that highly expressed in a variety of cancers and contributes to cell proliferation, migration, invasiveness, mobility, metastasis and EMT. However, its clinical significance and biological function in nasopharyngeal carcinoma (NPC) remain unknown up to now. Up-regulation of BMP2 was first observed in NPC cell lines by a genome-wide transcriptome analysis in our previous study. In this study, BMP2 mRNA was detected by qRT-PCR and data showed that it was upregulated in NPC compared with non-cancerous nasopharynx samples. Immunohistochemistry (IHC) analysis in NPC specimens revealed that high BMP2 expression was significantly associated with clinical stage, distant metastasis and shorter survival of NPC patients. Moreover, overexpression of BMP2 in NPC cells promoted cell proliferation, migration, invasiveness and epithelial-mesenchymal transition (EMT). Mechanistically, BMP2 overexpression increase phosphorylated protein level of mTOR, S6K and 4EBP1. Correspondingly, mTORC1 inhibitor rapamycin blocked the effect of BMP2 on NPC cell proliferation and invasion. In conclusion, our results suggest that BMP2 overexpression in NPC enhances proliferation, invasion and EMT of tumor cells through the mTORC1 signaling pathway.

Elevated FOXO6 expression correlates with progression and prognosis in gastric cancer.

The FOXO6 correlated with tumor progression in a wide range of carcinomas, yet little is known in gastric cancer. The expression of FOXO6 and matrix metallopeptidase 9 (MMP-9) was assessed by immunohistochemistry in 192 gastric carcinoma specimens. The correlation between FOXO6 expression with MMP-9, clinicopathological/prognostic value in gastric cancer was examined. FOXO6 overexpression was significantly associated with depth of invasion, lymph node metastasis and stage of disease. In univariate and multivariate analyses, FOXO6 was an independent prognostic factor for both overall survival (OS) and recurrence-free survival (RFS). Moreover, FOXO6 over-expression was correlated with poor prognosis in patients subgroups stratified by tumor size, depth of invasion and lymph node metastasis. FOXO6 expression was increased in both prominent serosal invasion group and lymph node metastasis group. In addition, FOXO6 expression was positively correlated with MMP-9 among 192 gastric cancer tissues. Patients with FOXO6 over-expression had poor OS and shorter RFS in low and high invasiveness groups. Furthermore, stratified analysis showed that the TNM stage I patients with high FOXO6 expression had poor prognosis than those with low FOXO6 expression. In conclusion, FOXO6 overexpression promotes tumor aggressiveness and prognosis, and could be a promising target for prognostic prediction in gastric cancer patients. CONDENSED ABSTRACT: The aim of this study was to analyze the role of FOXO6 in patients with gastric carcinoma. FOXO6 may play an important role on tumor invasion, metastasis and prognosis. It may also serve as a novel target for prognostic prediction.

Overexpression of Rab1B and MMP9 predicts poor survival and good response to chemotherapy in patients with colorectal cancer.

Rab1B has recently been reported to be involved in human cancer, but the role of Rab1B in colorectal cancer (CRC) remains unclear. In this study, we investigated the expression of Rab1B and MMP9 in CRC by qRT-PCR, immunoblot and immunohistochemistry and analyzed the clinical significance. The results show that Rab1B and MMP9 are increased at both mRNA and protein levels in CRC cell lines and tissues, as measured by qRT-PCR and immunoblotting. The high protein expression of Rab1B and MMP9 in 179 CRC tissues is associated with deep tumor invasion, lymph-node metastasis and advanced TNM stage. Survival analysis indicates that patients with overexpression of Rab1B or MMP9 have significantly worse overall survival and progression-free survival, but better response to chemotherapy than those with low expression of proteins, and that Rab1B is an independent prognostic factor for CRC patients. Furthermore, when Rab1B and MMP9 are combined into a new risk model, it has a remarkably better prediction of prognosis than each protein alone. In conclusion, Rab1B and MMP9 are potential prognostic biomarkers and their combination significantly improves predictive power for survival and chemotherapy response in CRC patients.

Prognostic impact of pretherapeutic gamma-glutamyltransferase on patients with nasopharyngeal carcinoma.

BACKGROUND: Gamma-glutamyltransferase (GGT) is a membrane-bound enzyme involved in the metabolism of glutathione. Studies suggested that GGT played an important role in the tumor development, progression, invasion and drug resistance and prognosis. The association between GGT and prognosis of patients with nasopharyngeal carcinoma (NPC) was unknown. This study was conducted to investigate the association of pretherapeutic serum level of GGT with clinical-pathological parameters and survival in patients with NPC. METHODS: Two hundred and twenty-two patients with NPC were recruited in this study and were stratified into two GGT risk groups (≤ 34.5 U/L, > 34.5 U/L). The association of pretherapeutic serum GGT levels with clinical-pathological parameters was examined. Univariate and multivariate survival analyses were performed. FINDINGS: The pretherapeutic serum level of GGT was not associated with gender, age, pathology, T stage, N stage, TNM stage, chemotherapy or radiotherapy in patients with NPC. Patients in the high-risk GGT group had a poorer survival than the low-risk GGT group (3-year overall survival, 74.2% vs. 50.2%, P = 0.001; 3-year progression-free survival, 76.4% vs. 47.1%, P < 0.001; 3-year loco-regional relapse-free survival, 76.4% vs. 51.3%, P < 0.001; 3-year distant metastasis-free survival, 89.5% vs. 66.4%, P < 0.001). Multivariate analysis suggested that patients in the high-risk GGT group had 2.117 (95% confidence interval [CI], 1.225 ∼ 3.659, P = 0.007) times the risk of death, 2.836 (95% CI, 1.765 ∼ 4.557, P < 0.001) times the risk of progression, 2.551 (95% CI, 1.573 ∼ 4.138, P < 0.001) times the risk of relapse, and 3.331 (95% CI, 1.676 ∼ 6.622, P < 0.001) times the risk of metastasis compared with those in the low-risk GGT group. CONCLUSION: The pretherapeutic serum level of GGT might serve as a novel independent prognostic factor for overall-survival, progression-free survival, loco-regional relapse-free survival and distant metastasis-free survival in patients with NPC.

Prognostic values of apoptosis-stimulating P53-binding protein 1 and 2 and their relationships with clinical characteristics of esophageal squamous cell carcinoma patients: a retrospective study.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer-related death, and new prognostic biomarkers are urgently needed. Apoptosis-stimulating P53-binding protein 1 (ASPP1) and 2 (ASPP2) have been reported to play important roles in the development, progression, metastasis, and prognosis of cancers, but their roles in ESCC have not been elucidated. In this study, we examined the expression of ASPP1 and ASPP2 in ESCC to evaluate their prognostic values. METHODS: The protein expression of ASPP1, ASPP2, and P53 in 175 specimens of ESCC was detected using immunohistochemical staining; their expression in cancerous and noncancerous tissues was scored according to the staining intensity and the percentage of stained cells. The associations of ASPP1, ASPP2, and P53 with clinicopathologic parameters, overall survival (OS), and disease-free survival (DFS) were analyzed. RESULTS: The protein expression levels of ASPP2 and P53 were significantly higher in cancerous tissues than in paired noncancerous tissues (P < 0.001), whereas the expression levels of ASPP1 in the two groups were similar. In ESCCs, ASPP1 expression was significantly associated with histological differentiation (P = 0.002) and invasive depth (P = 0.014); ASPP2 expression was associated with age (P = 0.029) and histological differentiation (P < 0.001); and P53 expression was associated with age (P = 0.021) and tumor size (P = 0.040). No correlations were found between ASPP1, ASPP2, and P53 expression. Survival analysis revealed that high ASPP2 expression was significantly associated with increased 5-year OS (P = 0.001) and DFS rates (P = 0.010) and that high P53 expression was significantly associated with a reduced 5-year DFS rate of ESCC patients (P = 0.015). Multivariate Cox analysis indicated that ASPP2 was an independent predictor of OS [hazard ratio (HR): 0.541, 95% confidence interval (CI) 0.363-0.804] and DFS (HR: 0.599, 95% CI 0.404-0.888) of ESCC patients and that P53 was an independent predictor of DFS (HR: 2.161, 95% CI 1.100-4.245). CONCLUSIONS: ASPP1 might be involved in the progression of ESCC, and ASPP2 was a potential prognostic biomarker of ESCC and should be evaluated in future studies.

Clinical significance and prognostic value of TRIM24 expression in esophageal squamous cell carcinoma.

Tripartite motif-containing 24 (TRIM24), a member of the transcription intermediary factor 1 family, is defined as a co-regulator with several nuclear receptors, such as RARα. TRIM24 has been reported to be involved in many cancers. In this study, we aimed to investigate the expression pattern and prognostic significance of TRIM24 and its relationship with RARα in esophageal squamous cell cancer (ESCC). Both mRNA and protein expression levels of TRIM24 were found to be significantly decreased in ESCC, as judged by qRT-PCR and western blot. Immunohistochemistry staining shows that the reduced TRIM24 protein is associated with lymph node metastasis (P=0.024), advance pathological TNM (pTNM) stage (P=0.046) and recurrence/metastasis (P=0.001). Upregulated TRIM24 protein predicts longer overall survival and disease-free survival (both P<0.001) and is an independent predictor for good prognosis (HR, 0.519; 95%CI, 0.341-0.788; P=0.002). TRIM24 expression has been proven remarkably to improve prediction of survival of pTNM stage in ESCC patients, especially in stage I and II. However, no significant relationship was found between TRIM24 and RARα expression levels. In conclusion, reduced TRIM24 protein is associated with poor survival in ESCC patients, suggesting TRIM24 protein is a potential prognostic biomarker for ESCC.

LncRNA ANRIL is up-regulated in nasopharyngeal carcinoma and promotes the cancer progression via increasing proliferation, reprograming cell glucose metabolism and inducing side-population stem-like cancer cells.

Long noncoding RNAs play a vital role in diverse biological processes such as embryonic development, cell growth, and tumorigenesis. In this study, we report that LncRNA ANRIL, which encodes a 3834-nt RNA that contains 19 exons at the antisense orientation of the INK4B-ARF-INK4A gene cluster, generally up-regulated in nasopharyngeal carcinoma [1]. In a cohort of 88 NPC patients, ANRIL was highly expressed in advanced-stage cancer. Multivariate analyses revealed that ANRIL expression could serve as an independent predictor of overall survival (P = 0.027) and disease-free survival (P = 0.033). Further investigation showed that knockdown of ANRIL significantly repressed NPC cell proliferation and transformation. We also found that ANRIL could induce the percentage of side population cells (SP cells) in NPC. To meet the urgent needs of energy provision, ANRIL can also reprogram glucose metabolism via increasing glucose uptake for glycolysis, which was regulated by the mTOR signal pathway to affect the expression of essential genes in glycolysis. We concluded that ANRIL could promote NPC progression via increasing cell proliferation, reprograming cell glucose metabolism and inducing side-population stem-like cancer cells. Our results also suggested that ANRIL may serve as a novel diagnostic or prognostic biomarker and a candidate target for new therapies in NPC.

Overexpressed HDAC4 is associated with poor survival and promotes tumor progression in esophageal carcinoma.

Histone deacetylases (HDACs) mediate histone deacetylation, leading to transcriptional repression, which is involved in many diseases, including age-related tissue degeneration, heart failure and cancer. In this study, we were aimed to investigate the expression, clinical significance and biological function of HDAC4 in esophageal carcinoma (EC). We found that HDAC4 mRNA and protein are overexpressed in esophageal squamous cell carcinoma (ESCC) tissues and cell lines. HDAC4 overexpression is associated with higher tumor grade, advanced clinical stage and poor survival. Mechanistically, HDAC4 promotes proliferation and G1/S cell cycle progression in EC cells by inhibiting cyclin-dependent kinase (CDK) inhibitors p21 and p27 and up-regulating CDK2/4 and CDK-dependent Rb phosphorylation. HDAC4 also enhances ESCC cell migration. Furthermore, HDAC4 positively regulates epithelial-mesenchymal transition (EMT) by increasing the expression of Vimentin and decreasing the expression of E-Cadherin/α-Catenin. Together, our study shows that HDAC4 overexpression is important for the oncogenesis of EC, which may serve as a useful prognostic biomarker and therapeutic target for this malignancy.

Reduced SOD2 expression is associated with mortality of hepatocellular carcinoma patients in a mutant p53-dependent manner.

The development and progression of hepatocellular carcinoma (HCC) is accompanied with persistent oxidative stress, but the molecular basis is not well defined. Superoxide dismutase 2 (SOD2) is an important mitochondrial antioxidant and a key aging factor. Here we investigated the expression and clinical significance of SOD2 in a large cohort of HBV-positive HCC tumors. Both SOD2 mRNA and protein are reduced in human primary HCCs compared with matching liver tissues. Consistently, the SOD2 DNA copy numbers are decreased in HCCs, providing a genetic basis for the decrease in SOD2 mRNA expression. Reduced SOD2 expression in HCCs is correlated with older age, larger tumor size, multiple tumor nodules and tumor emboli, and cancer recurrence. Moreover, low SOD2 expression is strongly associated with poor overall survival (OS) and recurrence-free survival (RFS). Univariate and multivariate Cox regression analyses indicates that SOD2 is an independent prognostic predictor for OS and RFS. Intriguingly, reduced SOD2 mRNA is strongly associated with poor survival in a separate cohort of HCC patients carrying mutant p53. Altogether, our results provide clinical evidence for the importance of SOD2 in tumor progression and mortality, and the close relationship of SOD2 and p53 in HCC.

DNA methylation regulates constitutive expression of Stat6 regulatory genes SOCS-1 and SHP-1 in colon cancer cells.

PURPOSE: Stat6 signaling is active in cancer cells and IL-4-induced Stat6 activities or Stat6 activational phenotypes vary among cancer cells. This study aimed at investigating possible mechanism(s) involved in the formation of varying Stat6 activities/phenotypes. METHODS: Stat6 regulatory genes, SOCS-1 and SHP-1, were examined for mRNA expression using RT-PCR, and their promoter DNA methylation was assayed by methylation-specific PCR in Stat6-phenotyped colon cancer cell lines. DNA methylation was then verified by sequencing. RT-PCR assay and Western blotting were used to detect the expression of SOCS-1 and SHP-1 after demethylation using 5-aza-2'-deoxycytidine. RESULTS: Compared with Stat6(null) Caco-2 cells, Stat6(high) HT-29 cells showed decreased constitutive expression of SOCS-1 and SHP-1, which correlated with DNA hypermethylation in these genes' promoters. Interestingly, demethylation in HT-29 cells recovered the constitutive expression of SOCS-1 and SHP-1. CONCLUSIONS: These findings suggest that DNA methylation controls the constitutive expression of negative Stat6 regulatory genes, which may affect Stat6 activities.