Chinese Clinical Oncology

The study on the mechanism by which circ_MTHFD2 promotes lung cancer resistance to pemetrexed through microRNA-124

XU Fei，MA Leina， FENG Lingxin，WU Yinjie， XU Xiaoyan， YU Zhuang

Chinese Clinical Oncology. 2017, 22 (11): 961.

Abstract ( 156 )

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Objective To investigate the effect of microRNA-124（miR124）mediated by circ_MTHFD2 on the resistance of lung cancer against pemetrexed.
Methods The pemetrexedresistant human lung cancer cell line was established by exposing pemetrexed repeatedly to highlevel concentration. The xenograft model of pemetrexed resistant nude mice by intratumoral injection was established. MiR-124 mimics， miR-124 inhibitors and negative controls were transfected into A549 and A549／PEM cells by Lipofectamine liposome method，and divided into miR-124 upregulation group， miR-124 inhibitory group and negative control group； then the sensitivity to pemetrexed was estimated by CCK-8 assay and flow cytometry. Real time fluorescent quantitative PCR（QPCR） and gene chip were used to detect the expression of miR-124 and circular RNA. Sequencing and bioinformatic analysis were used to detect the expression of circular RNA in different cells and tissue and to predict the binding sites between miR124 and circular RNA.Results The IC50 of parental strains A549 was （30.78±1.97）μmol／L， and the resistant strains A549／PEM was （913.53±14.1）μmol／L. The resistance index （RI） of pemetrexed-resistant human lung cancer cell line A549 named A549／PEM was 29.69±1.49. The expression of miR-124 in drug-resistant cell line A549／PEM was significantly decreased， which was about 145.952 times lower than that in A549 cells. Compared with the negative control group， the sensitivity to pemetrexed was significantly reduced in miR-124 inhibitor group， and the IC50 was（9.94±1.90）μmol／L and （80.45±3.50）μmol／L respectively， with significant difference between two groups（P＜0.05）. Flow cytometry showed that up-regulation of miR-124 expression could induce the apoptosis of A549 and 549／PEM cells compared with the control group. The sequencing indicated that the expression of many circular RNAs were upregulated in resistant cells and tissues， and up-regulated circ_MTHFD2 was proposed to bind miR-124. Conclusion Circ_MTHFD2 may be involved in the development of pemetrexed resistance in lung cancer by regulating the expression of miR-124.

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Study on the effects of CXCL12 on the radiosensitivity of cervical cancer

FU Zhichao， CHENG Huihua， LIAO Shaoguang， WANG Fengmei

Chinese Clinical Oncology. 2017, 22 (11): 968.

Abstract ( 105 )

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Objective To investigate the role of chemokine 12（CXCL12） in regulating the radiosensitivity of cervical cancer. Methods CXCL12 siRNA was transfected into cervical cancer HeLa cells by cationic liposome（siRNA transfection group）. The blank control group and the negative control group were set up. The HeLa cells in each group were irradiated with different doses （4， 8 Gy）. Cell viability was determined by CCK-8 assay. The apoptosis rate and expression of CD44 was detected by flow cytometry. ELISA method and realtime quantitative PCR （QPCR） were used to detect the change of CXCL12 expression. Results After 4 and 8 Gy irradiation, the survival rates of siRNA transfection group were 62.0％ and 44.0％， which were lower than 79.0% and 59.0% of the negative control group， and the difference was statistically significant （P＜0.05）. After 4 and 8 Gy irradiation, the apoptosis rates of siRNA transfection group were 28.0％ and 51.0％， which were higher than 21.0％ and 39.0％ of the negative contol group， and the difference was statistically significant （P＜0.05）. After 4 and 8 Gy irradiation, the expression of CD44 protein in the siRNA transfection group was 1.33 ±0.02 and 1.40±0.01， which was lower than 1.55 ±0.02 and 1.85 ±0.02 in the negative control group，and the difference was statistically significant （P＜0.05）. Conclusion Silencing CXCL12 can increase the radiosensitivity of cervical cancer cells by inhibiting cell proliferation and promoting apoptosis， and CXCL12 may be a new sensitizing target for cervical cancer radiotherapy.

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The effect of CXCR4 inhibitor on radiosensitization of triple negative breast cancer

TANG Xinyu， CAO Yuandong， SUN Xinchen

Chinese Clinical Oncology. 2017, 22 (11): 973.

Abstract ( 139 )

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Objective To investigate the radiation sensitivity of chemokine 12（CXCL12） receptor CXCR4 inhibitor AMD3100 on xenograft tumor of breast cancer of MDA-MB-231 cells in nude mice and the underlying mechanism. Methods Human breast cancer xenograft model on nude mice was established successfully， and the mice were divided into 4 groups： control group， AMD3100 treatment group， radiation group and combination group （AMD3100+radiation）， 9 mice each group. The size and weight of xenograft tumor were measured， the radiosensitization enhancement ratio was calculated and the xenograft tumor growth curve was depicted. The quantitative realtime PCR （QPCR） was used to detect the expression of CXCR4 and epidermal growth factor receptor （EGFR）. Western blotting was used to detect the protein expression of CXCR4， EGFR and matrix metalloproteinases-9 （MMP-9）. Results The radiosensitization enhancement ratio was 1:45. Compared with the control group， the gene relative expression of CXCR4 and EGFR in AMD3100 treatment group， radiotherapy group and combination group was down-regulated by 60％，45％，82％ and 56％，48％，73％， and the difference was statistically significant（P＜0.05）. The result by QPCR showed that both AMD3100 and radiotherapy could inhibit the expression of CXCR4 and EGFR （P＜0.05）， while AMD3100 and radiation combination could better inhibit the expression of CXCR4 and EGFR when compared with the AMD3100 single treatment group and radiotherapy group（P＜0.05）. The result of Western blotting showed that AMD3100 or radiotherapy could inhibit the expression of CXCR4， EGFR and MMP-9， AMD3100 and radiotherapy combination inhibited the expression of the three proteins more significantly （P＜0.05）.
Conclusion AMD3100 can enhance the radiosensitivity in nude mice xenografts of breast cancer， and the mechanism involves the down-regulation of CXCR4， EGFR and MMP-9.

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Analysis of the association of H19 gene polymorphisms with susceptibility to prostate cancer

CHEN Jianhui， LI Xiaofan， WENG Minggao， CAI Weizhong.

Chinese Clinical Oncology. 2017, 22 (11): 978.

Abstract ( 148 )

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Objective To investigate the association between single nucleotide polymorphisms （SNPs） of long noncoding RNA H19 and susceptibility to prostate cancer. Methods Peripheral venous blood samples were collected from 145 patients with prostate cancer following pathological diagnosis and 162 healthy controls from January 2013 to September 2016 in our hospital. According to the principle of minimum allele frequency＞0.05 and linkage disequilibrium parameter r2＞0.8， four TagSNPs （rs2839698， rs3024270， rs217727 and rs2735971） of H19 were screened. Genotyping was carried out by using TaqMan MGB allele typing kit. The genotype and allele distribution differences and HardyWeinberg balance of two groups in terms of TagSNPs were analyzed. The odds ratio （OR） and its 95％ confidence interval （95％CI） were used to estimate the relative risk of prostate cancer. Results Four TagSNPs of H19 in 145 cases of prostate cancer and 162 cases of healthy people were in Hardy-Weinberg equilibrium state. There was no significant difference in the distribution of rs3024270 and rs217727 genotypes and alleles between the prostate cancer group and the control group （P＞0.05）. As for the distribution of rs2839698， the frequencies of AA genotype and A allele were 28.3％（41／145） and 47.6％（138／290） in prostate cancer group， higher than 14.2％（23／162） and 36.1％（117／324） in the control group （P＜0.05）. As for the distribution of rs2735971， the frequencies of CC genotype and C allele were 35.2％（51／145） and 54.1％（157／290）， higher than 19.7％（32／162） and 386％（125／324） in the control group （P＜0.05）. Both rs3024270 and rs217727 have nothing to do with prostate cancer susceptibility. Compared with rs2839698 GG genotype， AA genotype increased risk of prostate cancer to 2.525 folds， while A allele increased to 1.606 folds compared with G allele. Compared with rs2735971 TT genotype， CC and TC+CC genotype increased risk of prostate cancer to 2.820 and 2.017 folds， respectively （P＜0.05）. For rs2735971， C allele increased risk of prostate cancer to 1.879 folds compared with T allele （P＜0.05）. Conclusion H19 rs2839698 and rs2735971 are associated with susceptibility to prostate cancer， and the risk of prostate cancer in individuals with mutant alleles is elevated， which is valuable for screening prostate cancer susceptible populations.

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Association of TOP2A with the efficacy of adjuvant chemotherapy and epirubicin in gastric cancer

LONG Weiguo， LI Xiaoqin， WANG Hongyu， REN Jin， CHEN Deyu， GU Hangang， WANG Deqiang.

Chinese Clinical Oncology. 2017, 22 (11): 984.

Abstract ( 104 )

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Objective To investigate the association of TOP2A with the efficacy of adjuvant chemotherapy and epirubicin in gastric cancer.
Methods Patients with gastric adenocarcinoma who had received radical gastrectomy of D2 and adjuvant chemotherapy after surgery were selected. The expression of TOP2A protein in paraffin-embedded tumor tissues was detected by immunohistochemistry， and its correlations with diseasefree survival （DFS） and overall survival （OS） of patients were analyzed.
ResultsA total of 109 patients were enrolled including 44 epirubicintreated patients. The expression level of TOP2A protein was not relative with clinicopathologic characteristics of gastric cancer（P＞0.05）. Kaplan-Meier survival analyses showed that the 3-year diseasefree survival rate and 3year overall survival rate in patients with low expression of TOP2A protein were higher than those with high expression （79.8％ vs. 57.1％ and 88.0％ vs. 65.0％， respectively； both P＜0.05）. In patients with gastric cancer treated with epirubicin adjuvant chemotherapy， such superiority associated with low expression of TOP2A protein was also observed for DFS （83.3％ vs. 50.0％； P＜0.05） and OS had a trend to be significantly different （91.7％ vs. 62.2％； P=0.068）. Furthermore， Multivariate Cox regression proportional hazard analysis showed that histological grade of Ⅲ （HR=3.02， 95％CI：1.41~6.46； P=0.004） and TOP2A high expression （HR=3.51， 95％CI：1.06~11.58； P=0.039） were the independent risk factor of OS in gastric cancer. Conclusion The TOP2A expression may be associated with the efficacy of adjuvant chemotherapy and epirubicin in gastric cancer， and it is a potential molecular marker for efficacy prediction.

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Expression of ALDH1A1 and ALDH6A1 in hilar cholangiocarcinoma and their clinical significance

XU Lin， YU Wenlong， YU Guanzhen， YU Lei

Chinese Clinical Oncology. 2017, 22 (11): 990.

Abstract ( 153 )

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Objective To investigate the expression of aldehyde dehydrogenase 1A1 （ALDH1A1） and aldehyde dehydrogenase 6A1 （ALDH6A1） in hilar cholangiocarcinoma tissues and their clinical significance.
Methods Forty-nine cases of hilar cholangiocarcinoma tissues and 10 cases of tumor-adjacent tissues were enrolled from 2005 to 2007. The expression of ALDH1A1 and ALDH6A1 was detected by immunohistochemical SP staining. The correlation of their expression and clinicopathological features as well as prognosis was evaluated. Results The high expression rates of ALDH1A1 and ALDH6A1 were 69.4％（34／49） and 44.9％（22／49），higher than 30.0％（3／10） and 10.0％（1／10） in tumor-adjacent tissues respectively （P＜0.05）. The expression of ALDH1A1 and ALDH6A1 were related to lymph node metastasis （P＜0.05）， but not to gender， age， TNM staging， tumor size， the depth of tumor invasion and nervous invasion （P＞0.05）. The median progressionfree survival （PFS） and median overall survival （OS） of ALDH1A1high expression patients were shorter than those of ALDH1A1low expression patients （12 months vs. 32 months， 12 months vs. 42 months，both P＜0.05）. The median OS of ALDH6A1high expression patients was shorter than that of ALDH6A1low expression patients （16 months vs. 23 months，P＜0.05）， whereas there was no significant difference between median PFS of ALDH6A1high expression and ALDH6A1low expression patients （15 months vs. 22 months，P＞0.05）. Cox multivariate analysis revealed that the depth of invasion and lymph node metastasis were independent factors influencing PFS， and the depth of invasion， lymph node metastasis and ALDH1A1 expression were independent factors influencing OS. Conclusion ALDH1A1 and ALDH6A1 were significantly upregulated in hilar cholangiocarcinoma tissues， and their expression is associated with the development of hilar cholangiocarcinoma. ALDH1A1 may be a new biomarker for predicting the prognosis of hilar cholangiocarcinoma.

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Expression of Wnt5a and ROR1 in osteosarcoma and their clinical significance

WANG Xingwen， ZHAO Xin， YI Zhigang， PU Yanchuan， MA Bing， WANG Jing， WANG Shuanke.

Chinese Clinical Oncology. 2017, 22 (11): 996.

Abstract ( 138 )

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Objective To investigate the expression and clinical significance of Wnt5a and receptor tyrosine kinase-like orphan receptor 1（ROR1） proteins in human osteosarcomatous tissues. Methods The expression of Wnt5a and ROR1 in 35 specimens of osteosarcoma tissues and 15 specimens of osteochondroma tissues was detected by immunohistochemical SP method. The correlation of Wnt5a and ROR1 expression with clinicopathological characteristics and prognosis of the patients with osteosarcoma was analyzed. Results The positive expression rates of Wnt5a and ROR1 in osteosarcoma tissues were 62.9％（22／35）and 57.1％（20／35），significantly higher than 13.3％（2／15）and 6.7％（1／15） of osteochondroma tissues, and the difference was statistically significant（P＜0.05）. The expression of Wnt5a and ROR1 was positively related to Enneking clinica1 stages and metastasis （P＜0.05）. The expression of Wnt5a was positively correlated with ROR1 protein （r=0.888， P＜0.001）. Kaplan-Meier analysis showed that the median overall survival of osteosarcoma patients with positive Wnt5a and ROR1 expression were 23 months and 27 months， significantly shorter than 41 months and 42 months of negative expression patients（P＜005）. Conclusion Wnt5a and ROR1 were high.y expressed in osteosarcoma and associated with the development and progression of osteosarcoma. Combined detection of Wnt5a and ROR1 is of great significance in judging the progress and prognosis of osteosarcoma.

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Tissues and sera levels of NRSN2 in nasopharyngeal carcinoma and their clinical significance

ZHANG Weidong， WU Wei， ZHANG Xiujuan.

Chinese Clinical Oncology. 2017, 22 (11): 1001.

Abstract ( 122 )

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Objective To investigate the tissues and sera levels of neurensin-2 （NRSN2） in nasopharyngeal carcinoma and their clinical significance.
MethodsFrom June 2014 to December 2016， 84 cases of nasopharyngeal carcinoma tissues and paired adjacent tissues diagnosed and treated in our hospital were collected. Meanwhile， 45 preoperative serum samples and 32 postoperative serum samples were collected and serum samples from 49 healthy subjects were used as controls. Real time fluorescent quantitative PCR （QPCR） was used to detect the levels of NRSN2 in cancer tissues and sera. The difference of NRSN2 levels between cancer tissues and adjacent tissues and the difference of serum levels of NRSN2 before and after operation were compared. The relationship between the NRSN2 levels and clinicopathological features in nasopharyngeal carcinoma was analyzed. The receiver operating characteristic curve （ROC） was used to evaluate the efficacy of tissue NRSN2 levels in the early diagnosis of nasopharyngeal carcinoma. Results NRSN2 level was 11.141±0.801 in 84 cases of nasopharyngeal carcinoma， higher than 1.165±0.071 of the adjacent tissues （P＜0.05）. The serum level of NRSN2 was 9.208±0.841 in 45 cases of nasopharyngeal carcinoma samples， higher than 1.127±0.084 of 49 healthy subjects （P＜0.05）. The serum level of NRSN2 was positively correlated with the tissue level of NRSN2 in patients with nasopharyngeal carcinoma （r=0.445， P=0.002）. The level of NRSN2 was not correlated with sex， age， N stage and neck lymph node metastasis （P＞0.05）， but correlated with T stage， TNM stage and VCA-IgA titer （P＜0.05）. The preoperative serum NRSN2 level of 32 nasopharyngeal carcinoma samples was 10.231±0.979， higher than 6.907±0.713 of postoperative serum samples （P=0.008）. The area under the curve of NRSN2 level was 0.954 （95％CI： 0.891~0.971）. The optimal cut-off value was 3.490 and the sensitivity and specificity of the cutoff value were 95.24％ and 100.0％， respectively. Conclusion In nasopharyngeal carcinoma， the level of NRSN2 was increased， and the serum level of NRSN2 decreased after operation. NRSN2 may participate in the occurrence and development of nasopharyngeal carcinoma. NRSN2 has a certain value in the evaluation and clinical diagnosis of nasopharyngeal carcinoma.

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Prognostic analysis of thoracic esophageal carcinoma patients with stage pT2-3N0-1M0 after surgery

LIU Yanhu， XUE Dong， LI Juan， TAN Zhenguo.

Chinese Clinical Oncology. 2017, 22 (11): 1006.

Abstract ( 123 )

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Objective To investigate the survival and its related factors of the patients with pathological stage pT2-3N0-1M0 thoracic esophageal squamous cell carcinoma after resection. Methods From January 2011 to March 2014 in the Second Affiliated Hospital of Nanjing Medical University， 127 patients with pathological stage pT2-3N0-1M0 thoracic esophageal squamous cell carcinoma after resection were enrolled. KaplanMeier analysis and Cox multivariate regression analysis were used to evaluate the postoperative survival and its related factors. Nomogram model was applied to implement for 1， 3， 5year survival rate of individual patients.
ResultsUntil the end of followup， the 1， 3， 5year survival rates and median overall survival （OS） were 81.8％， 54.3％， 38.4％ and 40.0 months（95％CI：32.285-47.715）， respectively. Cox multivariate analysis revealed that stage pT（pT2 and pT3）， pN（pN0 and pN1）， intravascular cancer embolus and tumor diameter（≤3 cm and＞3 cm）were the independent factors for OS， risk ratios of pT3， pN1， intravascular cancer embolus and tumor diameter＞3 cm were 2.207， 2.157， 1.758 and 1.607（P＜0.05）. Nomogram model could accurately predict the survival rate of pathological stage pT2-3N0-1M0 thoracic esophageal squamous cell carcinoma. Conclusion The survival of thoracic esophageal squamous cell carcinoma patients with stage pT2-3N0-1M0 after radical treatment shows significantly poor prognosis， the long-term survival of which is closely related to the depth of infiltration， lymph node metastasis， intravascular cancer embolus and tumor diameter， which is worthy of further study.

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Analysis of Mp-MRI based on PI-RADS v2 score combined with PSAD for middle-high grade prostate cancer

ZHANG Zhen， ZUO Mengzhe， WANG Jianliang.

Chinese Clinical Oncology. 2017, 22 (11): 1012.

Abstract ( 152 )

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Objective To analyze the value of multi-parameter magnetic resonance imaging （Mp-MRI） based on Prostate Imaging Reporting and Data System version 2 （PI-RADS v2） score combined with prostate specific antigen density （PSAD） for middlehigh grade prostate cancer（MHGPCa）.
MethodsThis retrospective study analyzed the datas of 227 patients of suspicious prostate disease， including 70 cases of MHGPCa， 23 cases of LGPCa and non-cancer of 134 cases who were all confirmed pathologically by puncture biopsies and underwent the high-resolution axial T2WI combined with DWI and DCE-MRI. The MRI images of the 227 patients were scored according to the PI-RADS v2 and the prostate volume and PSAD value were calculated. The univariate and multivariate analysis were performed for the observed indicators， including age， prostate volume， total prostate specific antigen （tPSA）， free-to-total PSA ratio （f／tPSA） and PI-RADS v2 score， to determine the independent predictors for MHGPCa. Then， the Logistic regression model was established using the independent predictors to jointly predict MHGPCa. The receiver operating characteristics （ROC） curves of the independent predictors and the model to diagnose MHGPCa were drew respectively to get the best threshold， and the differences of AUC values were compared to evaluate the diagnostic performance for MHGPCa. Results Among all the observed indicators， PI-RADS v2 score and PSAD were independent predictors for MHGPCa （P＜0.05）. The Logistic regression model established by PI-RADS v2 score combined with the PSAD to predict MHGPCa was as follows： Logit（P）=-5.514+0.7×PSAD+1.219×PI-RADS v2 score. The area under curve （AUC） value of the model （0.916） was higher than those of the PI-RADS v2 score and PSAD（0.882 and 0.892） and the differences between the model and PIRADS v2 score was statistically significant （P＜0.05）；but the difference of the AUC value between the model and PSAD was not statistically significant （P＞0.05） and the difference between PI-RADS v2 score and PSAD was not statistically significant （P＞0.05）. Conclusion The diagnositic performance of MpMRI based on PI-RADS v2 score combined with PSAD for MHGPCa is superior to that of PIRADS v2 score alone. Combined application of PI-RADS v2 score and PSAD can be popularized in clinical practice.

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标准刊号：	ISSN 1009-0460
	CN 32-1577/R