The gut microbiota, including probiotics and pathogenic microorganisms, is involved in ulcerative colitis (UC) by regulating pathogenic microorganisms and the production of intestinal mucosal antibodies. Huangqin decoction (HQD), a traditional Chinese formula chronicled in the Shanghan lun, has been recognized as an effective drug for UC, owing to its anti-inflammatory and anti-oxidative properties. In the present study, we investigated whether HQD ameliorates dextran sulphate sodium (DSS)-induced colitis through alteration of the gut microbiota. We found that HQD significantly inhibited colitis, alleviating the loss of body weight, disease activity index, colon shortening, tissue injury, and inflammatory cytokine changes induced by DSS treatment. Principal component analysis and principal co-ordinate analysis showed an obvious difference among the groups, with increased diversity in the DSS and DSS+HQD groups. Linear discriminant analysis effect size was used to determine differences between the groups. The relative abundance of Lactococcus was higher in the DSS+HQD group than in the DSS group, whereas Desulfovibrio and Helicobacter were decreased. Furthermore, the protective effect of HQD was attenuated only in antibiotic-treated mice. In conclusion, our results suggest that HQD could ameliorate DSS-induced inflammation through alteration of the gut microbiota.

Esophageal carcinoma (ESCA) is one of the most common malignancies worldwide, and its pathogenesis is complex. In this study, we identified differentially expressed miRNAs (DEMs) and genes (DEGs) of ESCA from The Cancer Genome Atlas (TCGA) database. The diagnostic values of DEMs were determined by receiver operating characteristic (ROC) analyses and validated based on data from Gene Expression Omnibus (GEO). The top five DEMs with the best diagnostic values were selected, and their potential targets were predicted by various in silico methods. These target genes were then identified among the DEGs from TCGA. Furthermore, the overlapping genes were subjected to protein-protein interaction (PPI) analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. The miRNA-transcription factor (TF) regulatory relations were determined using CircuitsDB and TransmiR. Finally, the regulatory networks of miRNA-TF and miRNA-gene were constructed and analyzed. A total of 136 DEMs and 3541 DEGs were identified in ESCA. The top five DEMs with the highest area under the receiver operating characteristic curve (AUC) values were miRNA-93 (0.953), miRNA-21 (0.928), miRNA-4746 (0.915), miRNA-196a-1 (0.906) and miRNA-196a-2 (0.906). The combined AUC of these five DEMs was 0.985. The KEGG analysis with 349 overlapping genes showed that the calcium signaling pathway and the neuroactive ligand-receptor interaction were the most relevant pathways. The regulatory networks of miRNA-TF and miRNA-gene, including 38 miRNA-TF and 560 miRNA-gene pairs, were successfully established. Our findings may provide new insights into the molecular mechanisms of ESCA pathogenesis. Future research will aim to explore the role of novel miRNAs in the pathogenesis and improve the early diagnosis of ESCA.

Tumor-associated macrophages (TAMs) play a crucial role in the regulation of local inflammatory and immune response of tumor microenvironment, being associated with worse outcome of several solid tumors. But the prognostic value of tumor-infiltrating TAMs in lung cancer is still controversial.

Approximately 50-75% of patients with serous ovarian carcinoma (SOC) experience recurrence within 18 months after first-line treatment. Current clinical indicators are inadequate for predicting the risk of recurrence. In this study, we used 7 publicly available microarray datasets to identify gene signatures related to recurrence in optimally debulked SOC patients, and validated their expressions in an independent clinic cohort of 127 patients using immunohistochemistry (IHC). We identified a two-gene signature including KCNN4 and S100A14 which was related to recurrence in optimally debulked SOC patients. Their mRNA expression levels were positively correlated and regulated by DNA copy number alterations (CNA) (KCNN4: p=1.918e-05) and DNA promotermethylation (KCNN4: p=0.0179; S100A14: p=2.787e-13). Recurrence prediction models built in the TCGA dataset based on KCNN4 and S100A14 individually and in combination showed good prediction performance in the other 6 datasets (AUC:0.5442-0.9524). The independent cohort supported the expression difference between SOC recurrences. Also, a KCNN4 and S100A14-centered protein interaction subnetwork was built from the STRING database, and the shortest regulation path between them, called the KCNN4-UBA52-KLF4-S100A14 axis, was identified. This discovery might facilitate individualized treatment of SOC.

Here we tested anti-tumor activity of KU-0060648 in preclinical hepatocellular carcinoma (HCC) models. Our results demonstrated that KU-0060648 was anti-proliferative and pro-apoptotic in established (HepG2, Huh-7 and KYN-2 lines) and primary human HCC cells, but was non-cytotoxic to non-cancerous HL-7702 hepatocytes. DNA-PKcs (DNA-activated protein kinase catalytic subunit) is an important but not exclusive target of KU-0060648. DNA-PKcs knockdown or dominant negative mutation inhibited HCC cell proliferation. On the other hand, overexpression of wild-type DNA-PKcs enhanced HepG2 cell proliferation. Importantly, KU-0060648 was still cytotoxic to DNA-PKcs-silenced or -mutated HepG2 cells, although its activity in these cells was relatively weak. Further studies showed that KU-0060648 inhibited PI3K-AKT-mTOR activation, independent of DNA-PKcs. Introduction of constitutively-active AKT1 (CA-AKT1) restored AKT-mTOR activation after KU-0060648 treatment in HepG2 cells, and alleviated subsequent cytotoxicity. In vivo, intraperitoneal (i.p.) injection of KU-0060648 significantly inhibited HepG2 xenograft growth in nude mice. AKT-mTOR activation was also inhibited in xenografted tumors. Finally, we showed that DNA-PKcs expression was significantly upregulated in human HCC tissues. Yet miRNA-101, an anti-DNA-PKcs miRNA, was downregulated. Over-expression of miR-101 in HepG2 cells inhibited DNA-PKcs expression and cell proliferation. Together, these results indicate that KU-0060648 inhibits HCC cells through DNA-PKcs-dependent and -independent mechanisms.

Sphingosine kinase 2 (Sphk2) has an oncogenic role in cancer. A recently developed first-in-class Sphk2 specific inhibitor ABC294640 displays antitumor activity in many cancer models. However, the role of Sphk2 and the antitumor activity of its inhibitor ABC294640 are not known in cholangiocarcinoma. We investigated the potential of targeting Sphk2 for the treatment of cholangiocarcinoma. We found that Sphk2 is overexpressed in five established human cholangiocarcinoma cell lines (WITT, HuCCT1, EGI-1, OZ and HuH28) and a new patient-derived cholangiocarcinoma cell line (LIV27) compared to H69 normal cholangiocytes. Inhibition of Sphk2 by ABC294640 inhibited proliferation and induced caspase-dependent apoptosis. Furthermore, we found that ABC294640 inhibited STAT3 phosphorylation, one of the key signaling pathways regulating cholangiocarcinoma cell proliferation and survival. ABC294640 also induced autophagy. Inhibition of autophagy by bafilomycin A1 or chloroquine potentiated ABC294640-induced cytotoxicity and apoptosis. In addition, ABC294640 in combination with sorafenib synergistically inhibited cell proliferation of cholangiocarcinoma cells. Strong decreases in STAT3 phosphorylation were observed in WITT and HuCCT1 cells exposed to the ABC294640 and sorafenib combination. These findings provide novel evidence that Sphk2 may be a rational therapeutic target in cholangiocarcinoma. Combinations of ABC294640 with sorafenib and/or autophagy inhibitors may provide novel strategies for the treatment of cholangiocarcinoma.

Tumor angiogenesis is essential in delivering oxygen and nutrients to growing tumors, and therefore considered as a hallmark of cancer. MicroRNAs (miRNAs) have been shown to play important roles in regulating tumor angiogenesis. MicroRNA-93-5p (miR-93-5p) has been identified as an oncogenic miRNA in a variety of human malignancies and involved in tumor angiogenesis in astrocytoma. However, the direct effect(s) of miR-93-5p on the biological behaviors of endothelial cells have not been investigated. Thus, in the present study we investigated the role(s) of miR-93-5p in regulating the functions of human umbilical vein endothelial cells (HUVECs). We found that triple negative breast cancer (TNBC) tissues with higher levels of miR-93-5p showed higher blood vessel density. Overexpression of miR-93-5p accelerated HUVECs proliferation and migration and promoted HUVECs lumen formation and sprouting in vitro, while blockade of miR-93-5p suppressed HUVECs migration and angiogenic capacity. The mechanistic studies revealed that miR-93-5p can promote angiogenic process through inhibiting epithelial protein lost in neoplasm (EPLIN) expression in HUVECs. In sum, our results have indicated that miR-93-5p promoted angiogenesis through down-regulating EPLIN and therefore represented a promising target for developing novel anti-angiogenic therapeutics.

Kidney renal papillary cell carcinoma (KIRP) accounts for 10%-15% of renal cell carcinoma (RCC), patients with KIRP tend to have a poor prognosis, and there was a lack of effective prognostic indicators for this type of cancer. Currently, owing to the availability of The Cancer Genome Atlas (TCGA), long non-coding RNAs (LncRNAs) have been discovered to indicate a prognostic value in some tumors. In that regard, we analyzed lncRNA-sequencing data of KIRP in TCGA, and among 780 differentially-expressed lncRNAs, we selected 37 lncRNAs which were able to assist the prognosis. In addition, by using the multivariate cox regression analysis, the prognosis index (PI) that consisted of 7 lncRNAs (including AFAP1-AS1, GAS6-AS1, RP11-1C8.7, RP11-21L19.1, RP11-503C24.1, RP11-536I6.2, and RP11-63A11.1) could predict the progression and outcomes of KIRP with accuracy. More importantly, the PI was considered an independent indicator for prognostication of KIRP. Moreover, having categorized patients with KIRP into cohorts of high risk and low risk, according to the PI, we found that the key genes and pathways varied in these two groups. Overall, these LncRNAs, especially the PI, may be conceived as biomarkers and helpful for determining the different pathological stages for KIRP patients. However, their biological functions need to be further confirmed.

Early studies indicated that selective inflammatory immune cells in the prostate tumor microenvironment might be able to influence prostate cancer (PCa) progression. Here we found treating PCa cells with androgen deprivation therapy (ADT) results in the recruitment of more mast cells, which might then increase PCa cell invasion via down-regulation of AR signals in 4 different PCa cell lines. Mechanism dissection revealed infiltrating mast cells could decrease AR transcription via modulation of the PRC2 complex with LncRNA-HOTAIR at the AR 5' promoter region in PCa cells. The consequences of suppressing AR may then increase PCa cell invasion via increased MMP9 expression and/or increased stem/progenitor cell population. The in vivo mouse model with orthotopically xenografted PCa CWR22Rv1 cells with/without mast cells also confirmed that infiltrating mast cells could increase PCa cell invasion via suppression of AR signals. Together, our results provide a new mechanism for the ADT-enhanced PCa metastasis via altering the infiltrating mast cells to modulate PCa AR-MMP9 signals and/or AR-stem/progenitor cell population. Targeting these newly identified inflammatory mast cells-AR signals may help us to better suppress PCa metastasis at the castration resistant stage.

Sustained cell growth and proliferation, one of the hallmarks of cancer, is considered to responsible for cancer-related deaths by disorganizing the balance of growth promotion and growth limitation. Aberrant activation of the Wnt/β-catenin signaling pathway leads to cell proliferation, growth and survival, and promotes the development of various human tumors, including hepatocellular carcinoma. Elucidating the molecular mechanism of this abnormality in hepatocellular carcinoma carcinogenesis may improve diagnostic and therapeutic strategies for this malignancy. Herein, we report that the expression of miR-432 was markedly downregulated in hepatocellular carcinoma cell lines and tissues, and upregulation of miR-432 inhibited, whereas downregulation of miR-432 enhanced the proliferation and tumorigenicity of hepatocellular carcinoma cells both in vitro and in vivo. Furthermore, miR-432 directly targeted and suppressed multiple regulators of the Wnt/β-catenin signaling cascade, including LRP6, TRIM29 and Pygo2, which subsequently deactivated Wnt/β-catenin signaling pathway. Finally, miR-432 expression was inversely correlated with three targets in clinical hepatocellular carcinoma samples. These results demonstrated that miR-432 functions as a tumor-suppressive miRNA by suppressing Wnt/β-catenin signaling activation and may represent a therapeutic target for hepatocellular carcinoma.

The Cancer Genome Atlas network has revealed that the 'mesenchymal' epithelial ovarian cancer (EOC) subtype represents the poorest outcome, indicating a crucial role of stromal cancer-associated fibroblasts (CAFs) in disease progression. The cooperative role of CAFs in EOC metastasis has long been recognized, but the mechanisms of stromal CAFs activation are still obscure. Therefore, we carried out an integrative analysis to identify the regulator genes that are responsible for CAFs activation in microdissected tumor stroma profiles. Here, we determined that myristoylated alanine-rich C-kinase substrate (MARCKS) was highly expressed in ovarian stroma, and was required for the differentiation and tumor promoting function of CAFs. Suppression of MARCKS resulted in the loss of CAF features, and diminished role of CAFs in supporting tumor cell growth in 3D organotypic cultures and in murine xenograft model. Mechanistically, we found that MARCKS maintained CAF activation through suppression of cellular senescence and activation of the AKT/Twist1 signaling. Moreover, high MARCKS expression was associated with poor patient survival in EOC. Collectively, our findings identify the potential of MARCKS inhibition as a novel stroma-oriented therapy in EOC.

This prospective study was designed to investigate the prognosis of preoperative blood-routine markers for esophageal cancer mortality by using data from the ongoing Fujian prospective investigation of cancer (FIESTA) study. Patients who received three-field lymphadenectomy for esophageal cancer between 2000 and 2010 were enrolled. Of 2535 patients with complete survival data, esophageal squamous cell carcinoma (ESCC) accounted for 94.5% (n = 2396). Here, only ESCC patients were analyzed, with the median follow-up time of 38.2 months (range: 0.5 to 180 months). Of 10 blood-routine markers evaluated, platelet count and red cell distribution width (RDW) were two significant predictors for ESCC mortality in men (adjusted hazard ratio or HR = 1.25 and 0.84, 95% confidence interval or CI: 1.08-1.22 and 0.75-0.93, P < 0.001 and P = 0.001, respectively), while in women only lymphocyte showed marginal significance. Based on individual results, a new derivate calculated as platelet count to RDW ratio (PRR) was created, and it was superior over other widely-evaluated derivates in men after adjustment (HR = 1.21, 95% CI: 1.13-1.30, P < 0.001), while there was no observable significance in women. In further stratified analyses, the prognosis of PRR for ESCC mortality was reinforced in men with tumor-node-metastasis stage III (HR, 95% CI, P: 1.18, 1.09-1.28, 0.001), invasion depth T3-T4 (1.17, 1.08-1.26, <0.001) or positive lymph node metastasis (1.37, 1.18-1.59, <0.001). Taken together, we created a new derivate PRR that was proven to be superior over other blood-routine markers and exhibited strong prognostic capability for ESCC mortality in Chinese men.

The Epstein-Barr virus (EBV) is associated with a variety of cancers, including gastric cancer, which has one of the highest mortality rates of all human cancers. Long non-coding RNAs (lncRNAs) have been suggested to have important causal roles in gastric cancer. However, the interaction between lncRNAs and EBV has not yet been studied. To this end, we sequenced 11,311 lncRNAs and 144,826 protein-coding transcripts from four types of tissue: one non-EBV-infected gastric carcinoma (EBVnGC) and its adjacent normal tissue, and one EBV-associated gastric carcinoma (EBVaGC) and its adjacent normal tissue. Five lncRNAs showed EBVaGC-specific expression; of those, one (SNHG8) was validated using real-time PCR in an independent cohort with 88 paired gastric cancer and adjacent tissue samples. To explore the functions of SNHG8, we identified its mRNA targets on the lncRNA-mRNA co-expression network of the Illumina Body Map, which contains the RNA sequencing data of mRNAs and lncRNAs from 16 normal human tissues. SNHG8 lncRNA was found to affect several gastric cancer-specific pathways and target genes of EBV. Our results reveal the intertwined tumorigenesis mechanisms of lncRNA and EBV and identify SNHG8 as a highly possible candidate biomarker and drug target of gastric cancer.

Somatic mutations found within the tyrosine kinase domain (TKD) of the human epidermal growth factor (HER) family of receptors have been implicated in the development and progression of non-small cell lung cancer (NSCLC). However, no conclusive reports have described pathogenic mutations in kinase-impaired HER3. Here, we report a case of an advanced chemotherapy-resistant NSCLC, harboring a novel HER3(V855A) somatic mutation homologous to the EGFR(L858R)activating mutation. Co-expression of HER3(V855A) and wild-type HER2 enhances ligand-induced transformation of murine and human cell lines, while HER-targeted inhibitors potently suppress mutant HER3 activity. Consistent with these observations, in silico computational modeling predicts that mutant V855A alters the kinase domain and c-terminal end of the HER3 protein. Taken together, these findings provide a basis for the clinical exploration of targeted therapies in HER3 mutant NSCLC and by extrapolation, in other cancers that more frequently carry somatic HER3 mutations.

The prognostic role of miR-204-5p (previous ID: miR-204) is varied and inconclusive in diverse types of malignant neoplasm. Therefore, the purposes of the study comprehensively explore the overall prognostic role of miR-204-5p based on high-throughput microRNA sequencing data, and to investigate the potential role of miR-204-5p via bioinformatics approaches.

To investigate the clinical role and biological function of cyclin-dependent kinase 5 (CDK5) in hepatocellular carcinoma (HCC), 412 surgically resected tissue samples (HCC, n=171; non-HCC=241) were obtained and analyzed with immunohistochemistry. The diagnostic and prognostic values of CDK5 expression levels in HCC were clarified. Moreover, RNA-seq data or microarray datasets from The Cancer Genome Atlas (TCGA) (HCC, n=374; normal, n=50) or other public databases (HCC, n=1864; non-tumor=1995) regarding CDK5 in HCC were extracted and examined. Several bioinformatic methods were performed to identify CDK5-regulated pathways. In vitro experiments were adopted to measure proliferation and apoptosis in HCC cells after CDK5 mRNA was inhibited in the HCC cell lines HepG2 and HepB3. Based on immunohistochemistry, CDK5 expression levels were notably increased in HCC tissues (n=171) compared with normal (n=33, P<0.001), cirrhosis (n=37, P<0.001), and adjacent non-cancerous liver (n=171, P<0.001) tissues. The up-regulation of CDK5 was associated with higher differentiation (P<0.001), metastasis (P<0.001), advanced clinical TNM stages (P<0.001), portal vein tumor embolus (P=0.003) and vascular invasion (P=0.004). Additionally, TCGA data analysis also revealed significantly increased CDK5 expression in HCC compared with non-cancerous hepatic tissues (P<0.001). The pooled standard mean deviation (SMD) based on 36 included datasets (HCC, n=2238; non-cancerous, n=2045) indicated that CDK5 was up-regulated in HCC (SMD=1.23, 95% CI: 1.00-1.45, P<0.001). The area under the curve (AUC) of the summary receiver operating characteristic (SROC) curve was 0.88. Furthermore, CDK5 knock-down inhibited proliferation and promoted apoptosis. In conclusion, CDK5 plays an essential role in the initiation and progression of HCC, most likely via accelerating proliferation and suppressing apoptosis in HCC cells by regulating the cell cycle and DNA replication pathways.

Lung squamous cell carcinoma (LUSC) accounts for a significant proportion of lung cancer and there have been few therapeutic alternatives for recurrent LUSC due to the lack of specific driver molecules. To investigate the prospective role of lncRNAs in the tumorigenesis and progression of LUSC, the aberrantly expressed lncRNAs were calculated based on The Cancer Genome Atlas RNA-seq data. Of 7589 lncRNAs with 504 LUSC cases, 884 lncRNAs were identified as being aberrantly expressed (|log2 fold change| >2 and adjusted P<0.05) by DESeq R. The top 10 lncRNAs with the highest diagnostic value were SFTA1P,LINC00968, LINC00961, LINC01572,RP1-78O14.1, FENDRR, LINC01314,LINC01272, GATA6-AS1, and MIR3945HG. In addition to the significant roles in the carcinogenesis of LUSC, several lncRNAs also played vital parts in the survival and progression of LUSC. SFTA1P, LINC01272, GATA6-AS1 and MIR3945HG were closely related to the survival time of LUSC. Furthermore, LINC01572 and LINC01314 could distinguish the LUSC at early stage from that at advanced stage. The prospective molecular assessment of key lncRNAs showed that a certain series of genes could be involved in the regulation network. Furthermore, the OncoPrint from cBioPortal indicated that 14% (69/501) LUSC cases with genetic alterations could be obtained, including amplification, deep deletion and mRNA upregulation. More interestingly, the cases with genetic alterations had a poorer survival as compared to those without alterations. Overall, the study propounds a potentiality for interpreting the pathogenesis and development of LUSC with lncRNAs, and provides a novel platform for searching for more capable diagnostic biomarkers for LUSC.

Resveratrol and caloric restriction (CR) are the powerful therapeutic options for anti-aging. Here, their comparative effect on longevity-associated gene silencing information regulator (SIRT1) were evaluated in vitro and in vivo. IMR-90 cells treated with 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) were applied to establish a cellular senescence model, and rats treated with D-galactose (D-gal) were used as an aging animal model. Resveratrol and CR exhibited similar anti-aging activities, evidenced by inhibiting senescence and apoptosis, and restoring cognitive impairment and oxidative damage. Moreover, they could up-regulate telomerase (TE) activity, increase expressions of SIRT1, forkhead box 3a (Foxo3a), active regulator of SIRT1 (AROS) and Hu antigen R (HuR ), but decrease p53 and deleted in breast cancer 1 (DBC1) levels. However, 10 μM resveratrol in vitro and the high dose group in vivo showed relatively stronger activities of anti-aging and stimulating SIRT1 level than CR. In conclusion, resveratrol and CR showed similar anti-aging activities on SIRT1 signaling, implicating the potential of resveratrol as a CR mimetic.

Notch1 maturation participates in apoptosis and inflammation following intracerebral hemorrhage (ICH). It has been reported that Botch bound to and blocked Notch1 maturation. Here we estimated the role of Botch in ICH-induced secondary brain injury and underlying mechanisms. Experimental ICH model was induced by autologous arterial blood injection in Sprague-Dawley rats, and cultured primary rat cortical neurons were exposed to oxyhemoglobin to mimic ICH in vitro. Specific small interfering RNAs and expression plasmids encoding wild type Botch and Botch with Glu115Ala mutation were exploited. The protein levels of Botch and Notch1 transmembrane intracellular domain (Notch1-TMIC) were increased within brain tissue around hematoma. Botch overexpression led to an increase in unprocessed Notch1 full-length form accompanied by a significant decrease in Notch1-TMIC, while Botch knockdown resulted in an approximately 1.5-fold increase in Notch1-TMIC. There were increased cell apoptosis, necrosis and neurobehavioral deficits after ICH, which was inhibited by Botch overexpression and enhanced by Botch knockdown. Double immunofluorescence showed a colocalization of Botch and Notch1 in the trans-Golgi. Overexpression of wild type Botch, but not Botch E115A mutant, led to an increase in the interaction between Botch and Notch1, reduced the formation and the nuclear localization of Notch1 intracellular domain, and attenuated cell apoptosis and inflammation. In conclusion, Botch exerts neuroprotection against neuronal damage via antagonizing the maturation of Notch1 in Glu115-denpendent manner. However, neuroprotection mediated by endogenous Botch is not enough to reverse ICH-induced secondary brain injury.

This study was performed to evaluate the prognostic significance of the pretreatment serum gamma-glutamyltransferase (GGT) levels in a Chinese cohort of patients with early-stage or locally advanced cervical cancer. The pretreatment serum GGT levels were examined in 290 cervical cancer patients with stage I-III disease and 230 healthy controls selected from a cancer-free population in the same region. Patients were assigned to normal or high-risk GGT groups, as previously described, and the GGT levels were correlated to clinicopathologic parameters and survival data. The GGT levels in cervical cancer patients were significantly higher than those in healthy controls (35.6 ± 29.1 vs. 24.1 ± 14.7 U/L, P < 0.001). In addition, the pretreatment serum GGT levels were associated with the histology type (P = 0.023), lymph node involvement (P = 0.040), stage (P = 0.029), recurrence (P = 0.015) and death (P = 0.005), but not with age (P = 0.432), tumor size (P = 0.067) or degree of differentiation (P = 0.901). Moreover, univariate survival analysis revealed that patients with high GGT levels tended to have poorer disease-free survival (DFS) [hazard ratio (HR), 1.721; 95% confidence interval (CI), 1.189-2.491; P = 0.004] and overall survival (OS) (HR, 1.929; 95% CI, 1.294-2.876; P = 0.001) compared to those with normal GGT levels. However, a multivariate Cox-regression model did not support these data (HR, 1.373; 95% CI, 0.925-2.039; P = 0.116 for DFS and HR, 1.357; 95% CI, 0.887-2.078; P = 0.160 for OS, respectively) after adjusting for other confounding variables. High pretreatment serum GGT was associated with more advanced tumor behavior, but could not serve as an independent prognostic indicator in patients with early-stage or locally advanced cervical cancer.