Up-regulation of KIF14 is a predictor of poor survival and a novel prognostic biomarker of chemoresistance to paclitaxel treatment in cervical cancer

Kinesin family member 14 (KIF14) is a member of kinesin family proteins which have been found to be dysregulated in various cancer types. However, the expression of KIF14 and its potential prognostic significance have not been investigated in cervical cancer. Real-time PCR was performed to assess the expression levels of KIF14 in 47 pairs of cervical cancer tissues and their matched normal tissues from patients who had not been exposed to chemotherapy as well as tissue samples from 57 cervical cancer patients who are sensitive to paclitaxel treatment and 53 patients who are resistant. The association between KIF14 expression levels in tissue and clinicopathological features or chemosensitivity was examined. Kaplan–Meier analysis and Cox proportional hazards model were applied to assess the correlation between KIF14 expression levels and overall survival (OS) of cervical cancer patients. KIF14 expression levels were significantly increased in cervical cancer tissues compared with matched non-cancerous tissues and it was higher in tissues of patients who are chemoresistant compared with those who are chemosensitive. KIF14 expression was positively associated with high tumour stage (P=0.0044), lymph node metastasis (P=0.0034) and chemoresistance (P<0.0001). Kaplan–Meier analysis showed that high KIF14 expression levels predicted poor survival in patients with (P=0.0024) or without (P=0.0028) paclitaxel treatment. Multivariate analysis revealed that KIF14 was an independent prognostic factor for OS. Our study suggests that KIF14 may serve as a predictor of poor survival and a novel prognostic biomarker of chemoresistance to paclitaxel treatment in cervical cancer.     

B3GNT3 Expression Is a Novel Marker Correlated with Pelvic Lymph Node Metastasis and Poor Clinical Outcome in Early-Stage Cervical Cancer

Background

The β1,3-N-acetylglucosaminyltransferase-3 gene (B3GNT3) encodes a member of the B3GNT family that functions as the backbone structure of dimeric sialyl-Lewis A and is involved in L-selectin ligand biosynthesis, lymphocyte homing and lymphocyte trafficking. B3GNT3 has been implicated as an important element in the development of certain cancers. However, the characteristics of B3GNT3 in the development and progression of cancer remain largely unknown. Thus, our study aimed to investigate the expression pattern and the prognostic value of B3GNT3 in patients with early-stage cervical cancer.

Methods

The mRNA and protein levels of B3GNT3 expression were examined in eight cervical cancer cell lines and ten paired cervical cancer tumors, using real-time PCR and western blotting, respectively. Immunohistochemistry (IHC) was used to analyze B3GNT3 protein expression in paraffin-embedded tissues from 196 early-stage cervical cancer patients. Statistical analyses were applied to evaluate the association between B3GNT3 expression scores and clinical parameters, as well as patient survival.

Results

B3GNT3 expression was significantly upregulated in cervical cancer cell lines and lesions compared with normal cells and adjacent noncancerous cervical tissues. In the 196 cases of tested early-stage cervical cancer samples, the B3GNT3 protein level was positively correlated with high risk TYPES of human papillomavirus (HPV) infection (P = 0.026), FIGO stage (P < 0.001), tumor size (P = 0.025), tumor recurrence (P = 0.004), vital status (P < 0.001), concurrent chemotherapy and radiotherapy (P = 0.016), lymphovascular space involvement (P = 0.003) and most importantly, lymph node metastasis (P = 0.003). Patients with high B3GNT3 expression had a shorter overall survival (OS) and disease-free survival (DFS) compared with those with low expression of this protein. Multivariate analysis suggested that B3GNT3 expression is an independent prognostic indicator for cervical cancer patients.

Conclusions

Our study demonstrated that elevated B3GNT3 expression is associated with pelvic lymph node metastasis and poor outcome in early-stage cervical cancer patients. B3GNT3 may be a novel prognostic marker and therapeutic target for the treatment of cervical cancer.     

Aberrant Expression of Osteopontin and E-Cadherin Indicates Radiation Resistance and Poor Prognosis for Patients with Cervical Carcinoma

Radiotherapy is the first-line treatment for all stages of cervical cancer, whether it is used for radical or palliative therapy. However, radioresistance of cervical cancer remains a major therapeutic problem. Consequently, we explored if E-cadherin (a marker of epithelial-mesenchymal transition) and osteopontin could predict radioresistance in patients with locally advanced cervical squamous cell carcinoma (LACSCC). Patients were retrospectively reviewed and 111 patients divided into two groups (radiation-resistant and radiation-sensitive groups) according to progression-free survival (PFS). In pretreated paraffin-embedded tissues, we evaluated E-cadherin and osteopontin expression using immunohistochemical staining. The percentage of patients with high osteopontin but low E-cadherin expression in the radiation-resistant group was significantly higher than those in the radiation-sensitive group (p<0.001). These patients also had a lower 5-year PFS rate (p<0.001). Our research suggests that high osteopontin but low E-cadherin expression can be considered as a negative, independent prognostic factor in patients with LACSCC ([Hazard ratios (95% CI) 6.766 (2.940, 15.572)], p<0.001).     

miR-1275 targets MDK/AKT signaling to inhibit breast cancer chemoresistance by lessening the properties of cancer stem cells

Chemoresistance is a major obstacle in the neoadjuvant chemotherapy (NCT) of locally advanced breast cancer (LABC). Identification of miRNAs as prognostic biomarkers may help overcome chemoresistance of breast cancer (BC). This study aimed to evaluate the expression level of miR-1275 in plasma samples and its biological functions in the chemoresistance of BC. The expression levels of miR-1275 in plasma samples and cells were measured by RT-qPCR. CRISPR/Cas9-mediated gene editing was used to construct miR-1275 knock-out cells in MCF-7. We found that miR-1275 was significantly downregulated in plasma from patients resistant to chemotherapy and in chemoresistant BC cell lines, while patients with low levels of miR-1275 showed poor overall survival. miR-1275 knock-out promoted chemoresistance in BC cells by increasing the properties of cancer stem cells (CSCs). Mechanistically, we identified that MDK was determined to be direct downstream protein of miR-1275 which initiated PI3K/Akt signaling in breast cancer cells. We demonstrated that the high expression level of miR-1275 in plasma predicted better response to NCT. The reduction of miR-1275 promoted BC cells chemoresistance by increasing CSCs properties via targeting MDK/AKT axis. The potential of miR-1275 as a new prognostic biomarker and therapeutic target of BC patients was identified.     

KIN enhances stem cell-like properties to promote chemoresistance in colorectal carcinoma

Chemotherapy is widely used in colorectal cancer (CRC) treatment, especially in advanced stage patients. However, it is inevitable to develop chemoresistance. Recently, cancer cells acquired stem cell-like properties or cancer stem cells (CSC) were proved to attribute to chemoresistance. Here, we found that KIN protein was elevated in CRC cell lines and tissue specimens as compared to normal controls. Upregulation of KIN positively correlates with the metastatic status of CRC patients. Patients with high KIN expression showed poor prognosis and were with a short survival time. Overexpression of KIN enhanced, while silencing KIN impaired, chemoresistance to oxaliplatin (Ox) or 5-fluorouracil (5-FU) in CRC cell lines. Further investigation demonstrated that overexpression of KIN rendered CRC cells enriching CSC markers and CSC phenotype, and silencing KIN reduced CSC markers and CSC phenotype. Our findings suggest that the KIN level may be a suitable marker for predicting chemotherapy response in CRC, and silencing KIN plus chemotherapy may be a novel therapy for CRC treatment.     

APRO家族基因在胃癌中的表达及预后意义

目的:基于大数据挖掘分析BTG/Tob抗增殖蛋白家族(anti-proliferativeprotein family,APRO)基因在胃癌组织的表达及其对胃癌患者预后的影响。方法:采用Oncomine数据库分析APRO家族6个成员在胃癌组织中的m RNA表达情况,通过Kaplan-Meier Plotter数据库进行胃癌患者总生存期的分析。结果:相比正常胃组织,BTG2在胃癌组织中呈低表达;BTG3在肠型胃癌组织中呈高表达,而在总体胃癌组织中呈低表达。BTG3低表达的患者总生存期较短;对5-氟尿嘧啶辅助化疗的胃癌患者,低表达BTG2的预后较差。结论:BTG2、BTG3的m RNA表达在胃癌和正常胃组织中有明显差异。BTG3低表达的胃癌患者预后较差;BTG2可能参与调节胃癌患者5-氟尿嘧啶治疗的敏感性。     

Synergistic Role between p53 and JWA: Prognostic and Predictive Biomarkers in Gastric Cancer

Expression of p53 appears to be correlated to prognosis in patients with malignancy, but its role in gastric carcinoma has remained controversial. Recently we reported that JWA, an ADP-ribosylation-like factor 6 interacting protein 5 (ARL6ip5), was both prognostic for overall survival and predictive for platinum-based treatment of gastric cancer. In this study, we aimed to investigate p53 expression as a prognostic and predictive marker in resectable gastric cancer, alone and in combination with JWA. Expression of p53 was examined in three large patient cohorts (total n = 1155) of gastric cancer. High expression of p53 was significantly correlated with unfavorable clinicopathologic parameters and decreased overall patient survival. Furthermore, patients with high p53 expression in tumors acquired remarkable survival benefit from adjuvant first-line platinum-based-chemotherapy. The synergy between p53 and JWA in predicting patient outcome was demonstrated, while no significantly elevated predictive value concerning chemotherapy was observed. Thus, p53 expression is a potent prognostic and predictive factor for resectable gastric cancer with adjuvant platinum-based chemotherapy. A combined effect of p53 with JWA as efficient prognostic indicators was found for the first time.     

Prognostic value of the post-operative red blood cell distribution width in patients with rectal cancer with neoadjuvant chemoradiation followed by surgery

Purposes: Several studies have reported that elevated red cell distribution width (RDW) is related to poor prognosis in several cancers; however, the prognostic significance of perioperative RDW in patients with rectal cancer that received neoadjuvant chemoradiation therapy (NACRT) is unclear.Methods: A total of 120 patients with rectal cancer who received NACRT followed surgery were retrospectively reviewed from Affiliated Cancer Hospital of Zhengzhou University between 2013 and 2015. Data for peripheral blood tests prior to the initiation of NACRT, before surgery and first chemotherapy after surgery were collected, respectively. The optimal cutoff values of RDW were determined by ROC analysis, respectively. The relationship between RDW and the prognosis of patients was evaluated by the Kaplan Meier method, respectively.Results: The post-operative RDW^High patients had significantly worse 5-year overall survival (OS, P=0.001) and disease-free survival (DFS, P<0.001) than the post-operative RDW^Low patients, respectively. Whereas high pre-operative RDW was the only marker correlated with worse DFS (P=0.005) than the pre-operative RDW^Low patients, no relationship was found between pre-RDW and prognosis (OS, P=0.069; DFS, P=0.133). Multivariate analysis showed post-operative RDW had better predictive value than pre-RDW and pre-operative RDW.Conclusion: Post-operative RDW might be a useful prognostic indicator in patients with rectal cancer received neoadjuvant chemoradiation.     

Increased Expression of TGFβR2 Is Associated with the Clinical Outcome of Non-Small Cell Lung Cancer Patients Treated with Chemotherapy

To investigate the prognostic significance of TGFβR2 expression and chemotherapy in Chinese non-small cell lung cancer (NSCLC) patients, TGFβR2 expression NSCLC was analyzed in silico using the Oncomine database, and subsequently analyzed with quantitative RT-PCR in 308 NSCLC biopsies, 42 of which were paired with adjacent non-neoplastic tissues. Our results show that TGFβR2 expression was also increased in NSCLC biopsies relative to normal tissue samples and correlated with poor prognosis. TGFβR2 expression was also significantly correlated with other clinical parameters such as tumor differentiation, invasion of lung membrane, and chemotherapy. Moreover, overall survival (OS) and disease free survival (DFS) was increased in patients with low TGFβR2 expressing NSCLC and who had undergone chemotherapy. Thus, high expression of TGFβR2 is a significant risk factor for decreased OS and DFS in NSCLC patients. Thus, TGFβR2 is a potential prognostic tumor biomarker for chemotherapy.     

子宫内膜癌组织PRDM1、KIF23蛋白表达与临床病理特征及预后的关系研究

目的:探讨子宫内膜癌组织PR结构域蛋白1(PRDM1)、驱动蛋白家族成员23(KIF23)蛋白表达与临床病理特征及预后的关系。方法:选择2012年4月至2015年8月期间于我院行手术治疗的80例子宫内膜癌患者作为研究对象。检测子宫内膜癌组织以及癌旁组织中PRDM1、KIF23蛋白表达。分析PRDM1、KIF23蛋白表达与临床病理特征的关系。分析不同PRDM1、KIF23蛋白表达患者5年总生存率的差异。分析子宫内膜癌患者预后的影响因素。结果:与癌旁组织相比,子宫内膜癌组织中PRDM1、KIF23蛋白表达阳性率上调(P<0.05)。有淋巴结转移以及FIGO分期Ⅲ期患者的PRDM1、KIF23蛋白表达阳性率明显高于无淋巴结转移以及FIGO分期Ⅰ~Ⅱ期患者,组间差异显著(P<0.05)。PRDM1、KIF23蛋白阳性患者的5年总生存率明显低于PRDM1、KIF23蛋白阴性患者,组间差异显著(P<0.05)。Cox比例风险回归分析结果显示:PRDM1、KIF23蛋白表达、淋巴结转移、FIGO分期是子宫内膜癌患者预后的影响因素(P<0.05)。结论:在子宫内膜癌当中PRDM1、KIF23蛋白表达阳性率升高,有淋巴结转移、FIGO分期较高的患者PRDM1、KIF23表达阳性率上调,PRDM1、KIF23表达阳性患者5年总生存率下降。     

Low expression of Beclin 1, associated with high Bcl-xL,predicts a malignant phenotype and poor prognosis of gastric cancer

Recent studies have suggested that dysregulation of autophagy plays a pivotal role in tumorigenesis. Here, we determined the prognostic value of autophagy-related protein Beclin 1 in gastric cancer. A total of 153 primary gastric cancer patients were subjected to analysis of Beclin 1 expression and survival prognosis. Among them, 68 patients were assigned randomly and used as a training set to generate a cutoff score for Beclin 1 expression by receive operating characteristic (ROC) curve analysis. The ROC-generated cutoff score was subjected to analyze the association of Beclin 1 with clinical characteristics and patient outcome. In a testing set (n = 85) and overall patients (n = 153), both univariate and multivariate analysis found that low expression of Beclin 1 predicted adverse overall survival and progression-free survival for gastric cancer patients. Furthermore, in each stage of gastric cancer patients, Beclin 1 expression was a prognostic indicator in patients with stage II, III and IV. Importantly, a reverse relationship between Beclin 1 and Bcl-xL expression was demonstrated. In patients of elevated Bcl-xL expression, a subset with lower Beclin 1 expression displayed an inferior overall survival and progression-free survival than those with higher Beclin 1 expression. Thus, our data demonstrated that low expression of Beclin 1, associated with high Bcl-xL, played as an independent biomarker, contributing to a more aggressive cancer cell phenotype and poor prognosis for gastric tumor.     

Low expression of Beclin 1, associated with high Bcl-xL, predicts a malignant phenotype and poor prognosis of gastric cancer

Recent studies have suggested that dysregulation of autophagy plays a pivotal role in tumorigenesis. Here, we determined the prognostic value of autophagy-related protein Beclin 1 in gastric cancer. A total of 153 primary gastric cancer patients were subjected to analysis of Beclin 1 expression and survival prognosis. Among them, 68 patients were assigned randomly and used as a training set to generate a cutoff score for Beclin 1 expression by receive operating characteristic (ROC) curve analysis. The ROC-generated cutoff score was subjected to analyze the association of Beclin 1 with clinical characteristics and patient outcome. In a testing set (n = 85) and overall patients (n = 153), both univariate and multivariate analysis found that low expression of Beclin 1 predicted adverse overall survival and progression-free survival for gastric cancer patients. Furthermore, in each stage of gastric cancer patients, Beclin 1 expression was a prognostic indicator in patients with stage II, III and IV. Importantly, a reverse relationship between Beclin 1 and Bcl-xL expression was demonstrated. In patients of elevated Bcl-xL expression, a subset with lower Beclin 1 expression displayed an inferior overall survival and progression-free survival than those with higher Beclin 1 expression. Thus, our data demonstrated that low expression of Beclin 1, associated with high Bcl-xL, played as an independent biomarker, contributing to a more aggressive cancer cell phenotype and poor prognosis for gastric tumor.     

High Expression of Heat Shock Protein 90 Is Associated with Tumor Aggressiveness and Poor Prognosis in Patients with Advanced Gastric Cancer

The heat shock protein 90 (HSP90) is overexpressed and highly associated with poor prognosis in many malignancies. However, the role of HSP90 in gastric cancer has not been thoroughly elucidated. The aim of this study is to investigate the relationship of HSP90 expression with clinicopathological parameters and prognosis in advanced gastric cancer, and estimate the alteration of HSP90 expression after neoadjuvant chemotherapy. HSP90 and matrix metallopeptidase 9 (MMP-9) antigen expression was evaluated by immunohistochemistry in 322 advanced gastric carcinoma samples. The relationships between HSP90 and clinicopathological parameters and prognosis were analyzed. The response of HSP90 level was assessed in chemotherapeutic effect in 54 patients received 1–2 cycles of neoadjuvant chemotherapy. The positive expression of HSP90 was found to be 69.6% in 322 advanced gastric carcinoma samples. HSP90 protein expression was significantly associated with depth invasion (P<0.001), lymph node metastasis (P<0.001) and stage of disease (P<0.001). The positive rates of HSP90 expression were higher in both prominent serosal invasion group (P<0.001) and lymph node metastasis group (P<0.001). Moreover, HSP90 was significantly correlated with MMP-9 among 322 gastric cancer tissues (P<0.001). In univariate and multivariate analyses, HSP90 was an independent prognostic factor for both recurrence-free survival (RFS) and overall survival (OS). These results suggested that HSP90 may play an important role on tumor invasion, metastasis and prognosis, and might act as a promising target for prognostic prediction.     

Matrix Metalloproteinase-14 Expression and Its Prognostic Value in Cervical Carcinoma

The objective of the study was to evaluate the expression of matrix metalloproteinase-14 (MMP-14) in cervical carcinoma and correlate its expression with clinicopathological parameters, recurrence, and survival of the patients. The expressions of MMP-14 in normal cervical mucosa and cervical carcinoma tissue were detected with immunohistochemistry. Survival analysis by the Kaplan–Meier method was performed to assess prognostic significance. The positive expression rate of MMP-14 in cervical carcinoma tissue was 81.6 %(111/136), and there was significant difference on their positive expression rates between in cervical carcinoma tissue and in normal cervical mucosa(22.4 %)(13/58)(P < 0.05);The positive expression rates of MMP-14 in patients with poor histologic differentiation, lymph node metastasis, and recurrence group were heightened. Using Kaplan–Meier analysis, a comparison of survival curves of low versus high expressions of MMP-14 revealed a highly significant difference in human cervical carcinoma tissue (P < 0.05), which suggests that overexpression of MMP-14 is associated with a worse prognosis. The MMP-14 which promotes angiogenes is associated with lymph node metastasis, vascular invasion, and poor prognosis of cervical carcinoma. The current study shows that MMP-14 may be an independent prognostic factor for cervical carcinoma patients.     

MyD88 predicts chemoresistance to paclitaxel in epithelial ovarian cancer

Introduction: Early identification of chemoresistance in patients with ovarian cancer is of utmost importance in order to provide them with the most appropriate therapy. Recently, we described the expression of MyD88 in ovarian cancer cells that were resistant to the cytotoxic agent paclitaxel. In addition to chemoresistance, in MyD88 positive ovarian cancer cells, paclitaxel stimulates growth and production of proinflammatory cytokines. The objective of this study was to determine the correlation of MyD88 expression in primary and recurrent epithelial ovarian cancers with the response to carboplatin and paclitaxel combination chemotherapy. Methods: Tumors are heterogeneous structures that contain different cell populations, thus rendering the identification of specific tumor markers difficult. Using laser capture microdissection, pure cancer cells were isolated from ovarian malignant tumors that were obtained from 20 patients at the time of surgery. The microdissected cells were evaluated for the expression of MyD88, FasL, and XIAP by western blot analysis. Results: Protein expression was observed in samples containing as low as 500 cells. The results were correlated with the clinical course of those patients. It was evident that MyD88 expression in ovarian cancer cells accurately predicts a poor response to paclitaxel chemotherapy as shown by a short progression-free interval and overall survival. Conclusion: We describe for the first time a molecular approach to identify paclitaxel chemoresistance. Toxicity from agents without therapeutic benefit can be avoided by identifying those patients who will not respond to a specific agent. Molecular markers will enable us to design individualized treatments and improve overall survival.     

Knock-down of glutaminase 2 expression decreases glutathione,NADH, and sensitizes cervical cancer to ionizing radiation

Phosphate-activated mitochondrial glutaminase (GLS2) is suggested to be linked with elevated glutamine metabolism. It plays an important role in catalyzing the hydrolysis of glutamine to glutamate. The present study was to investigate the potent effect of GLS2 on radioresistance of cervical carcinoma. GLS2 was examined in 144 cases of human cervical cancer specimens (58 radioresistant specimens, 86 radiosensitive specimens) and 15 adjacent normal cervical specimens with immunohistochemistry. HeLa cells were treated with a cumulative dose of 50 Gy X-rays, over 6 months, yielding the resistant sub-line HeLaR. The expressions of GLS2 were measured by Western blot. Radioresistance was tested by colony survival assay. Apoptosis was determined by flow cytometry. The levels of glutathione (GSH), reactive oxygen species (ROS), NAD⁺/NADH ratio and NADP⁺/NADPH ratio were detected by quantization assay kit. Xenografts were used to confirm the effect of GLS2 on radioresistance in vivo. The expressions of GLS2 were significantly enhanced in tumor tissues of radioresistant patients compared with that in radiosensitive patients. In vitro, the radioresistant cell line HeLaR exhibited significantly increased GLS2 levels than its parental cell line HeLa. GLS2 silenced radioresistant cell HeLaR shows substantially enhanced radiosensitivity with lower colony survival and higher apoptosis in response to radiation. In vivo, xenografts with GLS2 silenced HeLaR were more sensitive to radiation. At the molecular level, knock-down of GLS2 increased the intracellular ROS levels of HeLaR exposed to irradiation by decreasing the productions of antioxidant GSH, NADH and NADPH. GLS2 may have an important role in radioresistance in cervical cancer patients.     

Stage IV colon cancer patients without DENND2D expression benefit more from neoadjuvant chemotherapy

According to the EPOC study, chemotherapy could improve 5-year disease-free survival of stage IV colon cancer patients by 8.1%. However, more molecular biomarkers are required to identify patients who need neoadjuvant chemotherapy. DENND2D expression was evaluated by immunohistochemistry in 181 stage IV colon cancer patients. The prognosis was better for patients with DENND2D expression than patients without DENND2D expression (5-year overall survival [OS]: 42% vs. 12%, p = 0.038; 5-year disease-free survival: 20% vs. 10%, p = 0.001). Subgroup analysis of the DENND2D-negative group showed that patients treated with neoadjuvant chemotherapy achieved longer OS than patients without neoadjuvant chemotherapy (RR = 0.179; 95% CI = 0.054–0.598; p = 0.003). DENND2D suppressed CRC proliferation in vitro and in vivo. Downregulation of DENND2D also promoted metastasis to distant organs in vivo. Mechanistically, DENND2D suppressed the MAPK pathway in CRC. Colon cancer patients who were DENND2D negative always showed a worse prognosis and were more likely to benefit from neoadjuvant chemotherapy. DENND2D may be a new prognostic factor and a predictor of the need for neoadjuvant chemotherapy in stage IV colon cancer.Subject terms: Colon cancer, Tumour biomarkers