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Predictive value of k-ras and PIk3CA in non-small cell lung cancer patients treated with EGFR-TkIs: a systemic review and meta-analysis

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Cancer Biology & Medicine 2015年第2期12卷 126-139页

作者： Jie-Ying Chen Ya-Nan Cheng Lei Han Feng Wei Wen-Wen Yu Xin-Wei Zhang Shui Cao Jin-Pu Yu Department of Immunology Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Tianjin Key Laboratory of Cancer Immunology and Biotherapy Cancer Molecular Diagnostic Core Laboratory Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Tianjin Key Laboratory of Cancer Immunology and Biotherapy Biotherapy Center Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Tianjin Key Laboratory of Cancer Immunology and Biotherapy

Objective： A meta-analysis was performed to augment the insufficient data on the impact of mutative EGFR downstream phosphatidylinositol-3-kinase （PI3k） and mitogen-activated protein kinase （MAPk） pathways on the clinical efficiency of epidermal growth factor receptor tyrosine kinase inhibitor （EGFR-TkI） treatment of non-small cell lung cancer （NSCLC） patients. Methods： Network databases were explored in April, 2015. Papers that investigated the clinical outcomes of NSCLC patients treated with EGFR-TkIs according to the status of k-ras and/or PIk3CA gene mutation were included. A quantitative meta-analysis was conducted using standard statistical methods. Odds ratios （ORs） for objective response rate （ORR） and hazard ratios （HRs） for progression-free survival （PFS） and overall survival （OS） were calculated. Results： Mutation in k-ras significantly predicted poor ORR [OR =0.22; 95% confidence interval （CI）, 0.13-0.35], shorter PFS （HR =1.56; 95% CI, 1.27-1.92）, and shorter OS （HR =1.59; 95% CI, 1.33-1.91） in NSCLC patients treated with EGFR-TkIs. Mutant PIk3CA significantly predicted shorter OS （HR =1.83; 95% CI, 1.05-3.20）, showed poor ORR （Ok =0.70; 95% CI, 0.22-2.18）, and shorter PFS （HR = 1.79; 95% CI, 0.91-3.53） in NSCLC patients treated with EGFR-TkIs. Conclusion： k-ras mutation adversely affected the clinical response and survival of NSCLC patients treated with EGFR- TkIs. PIk3CA mutation showed similar trends. In addition to EGFR, adding k-ras and PIk3CA as routine gene biomarkers in clinical genetic analysis is valuable to optimize the effectiveness of EGFR-TkI regimens and identify optimal patients who will benefit from EGFR-TkI treatment.

关键词： Non-small cell lung cancer (NSCLC) tyrosine kinase inhibitor (TkI) targeted therapy k-ras PIk3CA meta-analysis

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Identification of effective siRNA against k-ras in human pancreatic cancer cell line MiaPaCa-2 by siRNA expression cassette

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World Journal of Gastroenterology 2005年第13期11卷 2026-2031页

作者： WeiWang Chun-YouWang Ju-HuaDong XiongChen MinZhang GangZhao DepartmentofPancreasSurgeryCenter XieheHospitalTongjiMedicalCollegeHuazhongUniversityofScienceandTechnologyWuhan430022HubeiProvinceChina DepartmentofCenterLab XieheHospitalTongjiMedicalCollegeHuazhongUniversityofScienceandTechnologyWuhan430022HubeiProvinceChina DepartmentofENT XieheHospitallongj1MedicalCollegeHuazhongUniversityofScienceandTechnologyWuhan430022HubeiProvinceChina DepartmentofNeurology XieheHospitalTongjiMedicalCollegeHuazhongUniversityofScienceandTechnologyWuhan430022HubeiProvinceChina

AIM: We shall construct the small interfering RNA (siRNA) expression cassette (SEC) targeting activated k-ras gene sequence, identify more effective siRNA sequence against k-ras gene in human pancreatic cancer cell line MiaPaCa-2 by SEC and reveal the anti-cancer effects of RNA interference (RNAi) and its therapeutic possibilities. METHODS: Three different sites of SECs were constructed by PCR. k1/siRNA,k2/siRNA and k3/siRNA are located at sites 194,491 and 327, respectively. They were transfected into MiaPaCa-2 cells by liposome to inhibit the expression of activated k-ras. In the interfering groups of sites 194 and 491, we detected the apoptosis in cells by FACS after they were incubated for 48 h, then we tested the alternation of k-ras gene in MiaPaCa-2 cells by RT-PCR immunofluorescence, respectively. RESULTS: Introduction of the kl/siRNA and k2/siRNA against k-ras into MiaPaCa-2 cells leads to increased apoptosis, and the number of apoptotic cells is increased compared with control cells. The tests of RT-PCR immunofluorescence show the effects of inhibiting expression of activated k-ras gene by RNA interference in the kl/siRNA and k2/siRNA groups. We also find that the introduction of k3/siRNA has no effect on MiaPaCa-2 cells. CONCLUSION: kl/siRNA and k2/siRNA can inhibit the expression of activated k-ras but k3/siRNA has no effect, demonstrating that kl/siRNA and k2/siRNA are effective sequences against k-ras gene and k3/siRNA are not. We conclude that specific siRNA against k-ras expression may be a powerful tool to be used therapeutically against human pancreatic cancer.

关键词： k-ras RNAi siRNA siRNA expression cassette

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Development of a novel multi-functional integrated bioconjugate effectively targeting k-ras mutant pancreatic cancer

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Journal of Pharmaceutical Analysis 2022年第2期12卷 232-242页

作者： Yang-Yang Wang Liang Li Xiu-Jun Liu Qing-Fang Miao Yi Li Meng-Ran Zhang Yong-Su Zhen Department of Pediatric Oncology Tianjin Medical University Cancer Institute and HospitalTianjin300060China NHC key Laboratory of Biotechnology of Antibiotics Department of OncologyInstitute of Medicinal BiotechnologyChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing100050China

Folate receptor(FR)overexpression occurs in a variety of cancers,including pancreatic *** addition,enhanced macropinocytosis exists in k-ras mutant pancreatic ***,the occurrence of intensive desmoplasia causes a hypoxic microenvironment in pancreatic *** this study,a novel FR-directed,macropinocytosis-enhanced,and highly cytotoxic bioconjugate folate(F)-human serum albumin(HSA)-apoprotein of lidamycin(LDP)-active enediyne(AE)derived from lidamycin was designed and prepared.F-HSA-LDP-AE consisted of four moieties:F,HSA,LDP,and AE.F-HSA-LDP presented high binding efficiency with the FR and pancreatic cancer *** uptake in wild-type cells was more extensive than in k-ras mutant-type *** in vivo optical imaging,F-HSA-LDP displayed prominent tumor-specific biodistribution in pancreatic cancer xenograft-bearing mice,showing clear and lasting tumor localization for 360 *** the MTT assay,F-HSA-LDP-AE demonstrated potent cytotoxicity in three types of pancreatic cancer cell *** also induced apoptosis and caused G2/M cell cycle arrest.F-HSALDP-AE markedly suppressed the tumor growth of AsPc-1 pancreatic cancer xenografts in athymic *** well-tolerated doses of 0.5 and 1 mg/kg,(i.v.,twice),the inhibition rates were 91.2%and 94.8%,respectively(Pk-ras mutant pancreatic cancer.

关键词： Pancreatic cancer Folate receptor Multi-functional Macropinocytosis-enhanced Bioconjugate k-ras PEGylation

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Expression of ki-67,p53,and k-ras in chronic pancreatitis and pancreatic ductal adenocarcinoma

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World Journal of Gastroenterology 2005年第43期11卷 6765-6769页

作者： Seok Jeong Don Haeng Lee Jung Il Lee Jin-Woo Lee kye Sook kwon Pum-Soo kim Hyung Gil kim Yong Woon Shin Young Soo kim Young Bae kim Division of Gastroenterology Department of Pathology

AIM： To examine surgical specimens of pancreas with either chronic pancreatitis or pancreatic cancer in order to study whether ductal hyperplasia and dysplasia in pancreas represent precursor lesions for pancreatic cancer. METHODS： We examined expression of ki-67, CEA, p53, and k-ras, in the surgical specimens of pancreas with adenocarcinomas （n = 11） and chronic pancreatitis （n = 12）. Cellular proliferation was assessed by ki-67 proliferation index using the proliferation marker ki-67. In specimens with pancreas cancer, we divided pancreas epithelium into normal （n = 7）, ductal hyperplasia （n = 3）, dysplasia （n = 4）, and cancerous lesion （n = 11） after hematoxylin and eosin staining, ki-67, and CEA immunohistochemical staining. In cases with chronic pancreatitis, the specimen was pathologically examined as in cases with pancreas cancer, and they were also determined as normal （n = 10）, ductal hyperplasia （n = 4）, or dysplasia （n = 5）. p53 and k-ras expression were also studied by immunohistochemical staining. RESULTS： In pancreatic cancer, the ki-67 index was 3.73±3.58 in normal site, 6.62±4.39 in ductal hyperplasia, 13.47：1：4.02 in dysplasia and 37.03±10.05 in cancer tissue, respectively. Overall, p53 was positive in normal ducts, ductal hyperplasia, dysplasia, and carcinoma cells in 0 of 14 （0%）, 0 of 7 （0%）, 7 of 9 （78%）, and 10 of 11 （91%）, respectively, and k-ras was positive in 0 of 8 （0%）, 1 of 3 （33%）, 4 of 6 （67%）, 4 of 5 （80%）, respectively. CONCLUSION： Our results favorably support the hypothesis that ductal hyperplasia and dysplasia of the pancreas might be precursor lesions for pancreas cancer. Further evaluation of oncogenes by the molecular study is needed.

关键词： ki-67 p53 k-ras Chronic pancreatitis Pancreatic ductal adenocarcinoma

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Clinical significance of k-ras and BRAF mutations in Chinese colorectal cancer patients

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World Journal of Gastroenterology 2011年第6期17卷 809-816页

作者： Hong Shen Ying Yuan Han-Guang Hu Xiao-Xian Ye Mo- Dan Li Xian Zhong Wei-Jia Fang Shu Zheng Department of Oncology Second Affiliated Hospital Zhejiang University College of Medicine Hangzhou 310009 Zhejiang Province China Department of Internal Medicine Bin Jiang Hospital Hangzhou 310052 Zhejiang Province China Department of Medical Oncology First Affiliated Hospital Zhejiang University College of Medicine Hangzhou 310003 Zhejiang Province China keyLaboratory of Cancer Prevention and Intervention of Ministry of Education Cancer Institute Second Affiliated Hospital Zhejiang University College of Medicine Hangzhou 310009 Zhejiang Province China

AIM:To identify and assess mutations in the k-ras and BRAF genes in a cohort of Chinese patients with colorectal cancer (CRC) for their association with various clinicopathological parameters and ***:Genomic DNA was isolated from frozen *** analysis was conducted to detect mutations in the k-ras (codons 12,13,and 61) and BRAF genes (codon 600).Statistical analysis was carried out using SPSS-15.0 ***:Among the 118 colorectal cancer patients,we detected 41 (34.7%) mutations in the k-ras *** frequencies at codon 12 and codon 13 were 23.7% (28/118) and 10.2% (12/118),*** one patient harbored a point mutation at codon 61 (0.8%,1/118).Gender was the only factor that showed an obvious relationship with k-ras gene mutation (female 44.7% vs male 28.2%,P=0.037).Other clinicopathological features,such as age,location of the tumor,tumor differentiation,Tumor,Node and Metastases classification,and the Union for International Cancer Control staging,showed no positive relationship with k-ras gene *** significant correlation was observed between the presence of k-ras mutations (codons 12,13,and 61) and the survival of the *** mutations were rare,and only two patients (1.7%) harbored a detectable mutation at codon ***:k-ras gene mutation is a common event in our 118 Chinese CRC patients,with an obvious relationship with ***,it seems not to be an independent prognostic factor in CRC *** BRAF gene is rarely mutated in Chinese CRC patients.

关键词： k-ras BRAF Colorectal cancer Mutation

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Genetic changes of p53,k-ras,and microsatellite instability in gallbladder carcinoma in high-incidence areas of Japan and Hungary

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World Journal of Gastroenterology 2008年第1期14卷 70-75页

作者： Masayuki Nagahashi Yoichi Ajioka Istvan Lang Zoltan Szentirmay Miklos kasler Hiroto Nakadaira Naoyuki Yokoyama Gen Watanabe ken Nishikura Toshifumi Wakai Yoshio Shirai katsuyoshi Hatakeyama Masaharu Yamamoto Division of Molecular and Diagnostic Pathology Niigata University Graduate School of Medical and Dental Sciences Niigata 951-8510 Japan Department of Medical Oncology "B" National Institute of Oncology Budapest H-1122 Hungary Department of Molecular Pathology National Institute of Oncology Budapest H-1122 Hungary Department of Head and Neck Surgery National Institute of Oncology Budapest H-1122 Hungary Department of Nursing Faculty of Nursing Social Welfare and Psychology Niigata Seiryo University Niigata 951-8510 Japan Division of Digestive and General Surgery Niigata University Graduate School of Medical and Dental Sciences Niigata 951-8510 Japan Department of Community Preventive Medicine Niigata University Graduate School of Medical and Dental Sciences Niigata 951-8510 Japan

AIM： To disclose geographic differences in genetic changes involved in gallbladder carcinogenesis between two distinct high-incidence areas of Japan and Hungary. METHODS： We examined 42 cases of gallbladder carcinoma： 22 Japanese and 20 Hungarian cases, p53 mutations at exons 5 to 8 and k-ras mutations at codon 12 were tested by direct sequencing. Microsatellite instability was determined from fluorescent dye-labeled PCR amplifications of flve-microsatellite markers （BAT-25, BAT-26, D2S123, DSS346, and D17S250）. RESULTS： Mutations of p53 were detected in 11 of 22 Japanese cases and 6 of 18 Hungarian cases （11/22 vs 6/18, P = 0.348）. Transition at CpG sites was found in none of 11 Japanese cases and 2 of 6 Hungarian cases; the difference was marginally significant （0/11 vs 2/6,P = 0.110）. k-ras mutations were detected in only one of the Hungarian cases. Eight of 19 （42.1%） ]apanese cases were MSI-high （presence of novel peaks in more than one of the five loci analyzed）, whereas only 1 of 15 （6.7%） Hungarian cases was MSI-high （P = 0.047）. CONCLUSION： It appears that the p53 mutations and MSI differ in patients with gallbladder carcinoma between two distinct high-incidence areas. Geographic variation might exist in the process of gallbladder carcinogenesis.

关键词： Gallbladder Gallbladder Neoplasms k-ras Microsatellite instability p53

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Enhanced therapeutic effects for human pancreatic cancer by application k-ras and IGF-IR antisense oligodeoxynucleotides

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World Journal of Gastroenterology 2008年第33期14卷 5176-5185页

作者： Yong-Mei Shen Xiao-Chun Yang Chen Yang Jun-kang Shen Radioimmunoassay Center & Clinical Laboratory the Second Affiliated Hospital of Soochow University Suzhou 215004 Jiangsu Province China Department of MRI the Second Affiliated Hospital of Soochow University Suzhou 215004 Jiangsu Province China Radioimmunoassay Center the Municipal Hospital of Suzhou Suzhou 215002 Jiangsu Province China

AIM: To investigate the combined effects of k-ras antisense oligodeoxynucleotide (k-ras ASODN) specif ic to GTT point mutation at codon 12 and type Ⅰ insulin-like growth factor receptor (IGF-IR) antisense oligodeoxynucleotide (IGF-IR ASODN) on proliferation and apoptosis of human pancreatic cancer Patu8988 cells in vitro and in vivo. METHODS: k-ras gene point mutation and its style at codon 12 of human pancreatic cancer cell line Patu8988 were detected by using polymerase chain reaction with special sequence primers (PCR-SSP) and sequence analysis. According to the mutation style, k-ras mutation ASODN specifi c to k-ras point mutation at codon 12 was designed and composed. After k-ras ASODN and IGF-IR ASODN treated on Patu8988 cells respectively or cooperatively, the proliferation and morphological change of Patu8988 cells were analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony forming assay andtransmission electron microscopy; the expression of k-ras and IGF-IR mRNA and protein in the treated cells was measured by reverse-transcript polymerase chain reaction (RT-PCR) and flow cytometry respectively; apoptosis was determined by flow cytometry. The combined antitumor activity of k-ras ASODN and IGF-IR ASODN was evaluated in BALB/c nude mice bearing human pancreatic cancer inoculated with Patu8988 cells. RESULTS: The results of PCR-SSP and sequence analysis showed that the human pancreatic cancer cell line Patu8988 had point mutation at codon 12, and the mutation style was GGT→GTT. 2-32 μg/mL k-ras ASODN and 2-32 μg/mL IGF-IR ASODN could inhibit Patu8988 cells' growth, induce apoptosis and decrease the expression of k-ras and IGF-IR mRNA and protein alone. However, there was much more effective inhibition of growth and induction of apoptosis by their combination than by each one alone. In tumor bearing mice, the combination of k-ras ASODN and IGF-IR ASODN showed a signif icant inhibitory effect on the growth of transplanted pa

关键词： Pancreatic cancer Antisense oligodeoxy-nucleotide k-ras Type I insulin-like growth factor receptor Patu8988

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Comparative study of mutations in SNP loci of k-ras, hMLH1 and h MSH2 genes in neoplastic intestinal polyps and colorectal cancer

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World Journal of Gastroenterology 2014年第48期20卷 18338-18345页

作者： Zhi-Hui Yan Li-Hong Cui Xiao-Hui Wang Chao Li Xing He Department of Gastroenterology Navy General Hospital of PLA

AIM: To clarify the molecular mechanism involved in pathogenesis of colorectal cancer as well as clinical significance of genetic analysis of histological samples.

关键词： Neoplastic intestinal polyp Colorectal cancer Single nucleotide polymorphisms k-ras hMLH1 hMSH2

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Diagnostic accuracy of k-ras mutation for pancreatic carcinoma:a meta-analysis

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Hepatobiliary & Pancreatic Diseases International 2013年第5期12卷 458-464页

作者： Shang-Long Liu Ge Chen Yu-Pei Zhao Wen-Ming Wu Tai-Ping Zhang Department of General Surgery Peking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical College

BACkGROUND:The conventional tests for the diagnosis of early stage pancreatic carcinoma are not *** metaanalysis is to evaluate the accuracy of k-ras mutation for the diagnosis of pancreatic *** SOURCES:A systemic search of all relevant literature was performed in Web of Science,EMBASE,Cochrane Database,and MEDLINE(PubMed as the search engine) prior to June 1,***-four studies fulfilled the inclusion criteria and data were pooled for ***:The pooled estimates for k-ras mutation in diagnosis of pancreatic carcinoma were as follows:sensitivity 0.68(95% CI:0.66-0.71),specificity 0.87(95% CI:0.85-0.88),positive likelihood ratio 4.54(95% CI:3.47-5.94),negative likelihood ratio 0.37(95% CI:0.30-0.44) and diagnostic odds ratio 14.90(95% CI:10.02-22.15).Summary receiver operating characteristic analysis demonstrated that the maximum joint sensitivity and specificity was 0.79,and the overall area under the curve was ***:Diagnostic accuracy of k-ras mutation was not superior to that of conventional ***,k-ras mutation analysis alone is not recommended for the diagnosis of pancreatic carcinoma.

关键词： cancer diagnosis k-ras pancreatic carcinoma meta-analysis

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Regulation of CD137 expression through k-ras signaling in pancreatic cancer cells

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Cancer Communications 2019年第1期39卷 379-389页

作者： Christophe Glorieux Peng Huang Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhou 510060GuangdongP.R.China

Background:The interaction between CD137 and its ligand(CD137L)plays a major role in the regulation of immune functions and affects cancer ***137 is a cell surface protein mainly located on activated T cells,and its regulation and functions in immune cells are well ***,the expression of CD137 and its regulation in cancer cells remain poorly *** main purposes of this study were to examine the expression of CD137 in pancreatic cancer cells and to investigate its underlying ***:Cells containing inducible k-rasG12V expression vector or with different k-ras mutational statuses were used as in vitro models to examine the regulation of CD137 expression by *** molecular assays were employed to explore the regulatory *** specimens from 15 pancreatic cancer patients and serum samples from 10 patients and 10 healthy donors were used to test if the expression of CD137 could be validated in clinical ***:We found that the CD137 protein was expressed on the cell surface in pancreatic cancer tissues and cancer cell ***-linked immunosorbent assay revealed no difference in the levels of secreted CD137 in the sera of patients and healthy *** using the k-ras inducible cell system,we further showed that oncogenic k-ras up-regulated CD137 through the activation of MAPk(mitogen-activated protein kinases)and NF-κB(nuclear factor kappa-light-chain-enhancer of activated B cells)pathways,as evidenced by significantly reduced CD137 mRNA expression led by genetic silencing of MAPk1 and p65,the key proteins involved in the respective ***-more,we also found that the NF-κB pathway was mainly stimulated by the k-ras-induced secretion of interleukin-1α(IL-1α)which promoted the transcription of the CD137 gene in pancreatic cancer cell *** of the TCGA(the cancer genome atlas)database also revealed a significant correlation between IL-1αand CD137 expression(r=0.274)in tumor s

关键词： CD137 k-ras IL-1α(interleukin-1 alpha) MAPk(mitogen-activated protein kinases) NF-κB(nuclear factor kappa-light-chain-enhancer of activated B cells) Pancreatic cancer Oxidative stress Soluble CD137

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