富含半胱氨酸的酸性分泌蛋白与肿瘤相关性研究进展

目的:总结富含半胱氨酸的酸性分泌蛋白(SPARC)在肿瘤发生发展中的作用和对肿瘤信号传导通路的调节功能.方法:应用NCBI的PubMed全文数据库检索系统和CNKI检索系统,以“SPARC、侵袭、凋亡、血管形成和信号传导”为关键词,检索1995-01-2011-12相关文献352篇.纳入标准:1)SPARC;2)肿瘤;3)信号传导通路,包括MAPK、ILK和FAK信号通路;4)血管生成与侵袭.根据纳入标准分析32篇文献.结果:SPARC是一种在机体内广泛分布的小分子酸性糖蛋白,在肿瘤组织中肿瘤细胞和宿主细胞都有表达和分泌.SPARC功能非常复杂且具有组织特异性,肿瘤组织中的SPARC能够调节基质细胞和肿瘤细胞的功能,能够通过对肿瘤细胞表面的整合素的影响而激活ILK、FAK、AKT和MAPK等下游通路,从而最终调控肿瘤的生长和侵袭.结论:SPARC对不同肿瘤的生长、侵袭、血管形成和信号通路以不同的方式发挥重要影响,对SPARC的深入研究,将为不同肿瘤治疗提供新的策略和方法.     

Knockdown of secreted protein acidic and rich in cysteine (SPARC) expression diminishes radiosensitivity of glioma cells

Secreted protein acidic and rich in cysteine (SPARC) has been shown to play an important role in the promotion of glioma. In this study, we investigated the effects of downregulated SPARC expression on the radiosensitivity of human glioma U-87MG cells and its possible mechanism. With a small-interfering RNA (siRNA) expression plasmid vector targeting SPARC, we obtained the stably transfected cells in which the expression of SPARC was successfully downregulated. Then, the cells were irradiated with 60Co-γ-rays and analyzed by several methods, such as clonogenic assay, flow cytometry, comet assay, and western blotting. Clonogenic assay showed that downregulation of SPARC expression enhanced cell survival after radiation. Flow cytometry analysis indicated that SPARCsiRNA decreased cell apoptosis responding to irradiation. Analysis of signaling molecules with western blotting showed that the level of Akt phosphorylation was increased in irradiated U-87MG/SPARCsiRNA cells. Further, cell-cycle analysis by flow cytometry showed enhanced G2 accumulation in U-87MG/SPARCsiRNA cells after irradiation. Comet assay revealed that SPARCsiRNA promoted the repair of radiation-induced DNA damage. Our results suggest that inhibition of SPARC expression may diminish the radiosensitivity of human glioma U-87MG cells. One of the mechanisms for this effect may be associated with the reduced cell apoptosis responding to radiation, which may be contributed by the phosphoinositide 3-kinase/AKT pathway activation. Moreover, enhanced G2 accumulation and increased DNA repair may also account for the decreased radiosensitivity.     

The role of MMP-9 in the anti-angiogenic effect of secreted protein acidic and rich in cysteine

Background:

Secreted protein acidic and rich in cysteine (SPARC), a matricellular glycoprotein, modulates cellular interaction with the extracellular matrix and is capable of altering the growth of various cancers. We therefore sought to determine the effect of SPARC expression on medulloblastoma tumour growth and angiogenesis.

Methods:

To this extent, we selected three SPARC full-length cDNA overexpressed clones (Daoy-SP). Consequences of SPARC overexpression were studied in terms of cell growth, angiogenesis using co-culture assay in vitro, dorsal skin-fold chamber assay in vivo, PCR Array for human angiogenic genes, as well as western blotting for angiogenic molecules and tumour growth, in an orthotopic tumour model.

Results:

The SPARC protein and mRNA levels were increased by approximately three-fold in Daoy-SP cells compared with parental (Daoy-P) and vector (Daoy-EV) controls. Daoy-SP clones reduced tumour cell-induced angiogenesis in vitro and in vivo, and formed small tumours with fewer blood vessels when compared with controls. Matrix metalloprotease-9 (MMP-9) and vascular endothelial growth factor (VEGF) expression were decreased in Daoy-SP clones. Further, inhibition of MMP-9 expression caused SPARC-mediated inhibition of angiogenesis and tumour growth as MMP-9 rescued SPARC-mediated anti-angiogenic effect in vitro and tumour growth inhibition in vivo.

Conclusion:

Overexpression of SPARC decreases angiogenesis, which leads to decreased tumour growth. Further, the role of MMP-9 could be attributed to the anti-angiogenic effect of SPARC.     

A proteomics-based approach identifies secreted protein acidic and rich in cysteine as a prognostic biomarker in malignant pleural mesothelioma

Background:

We aimed to identify prognostic blood biomarkers using proteomics-based approaches in malignant pleural mesothelioma (MPM).

Methods:

Plasma samples from 12 MPM patients were used for exploratory mass spectrometry and ELISA analyses. The significance of secreted protein acidic and rich in cysteine (SPARC) was examined in sera from a Dutch series (n=97). To determine the source of the circulating SPARC, we investigated SPARC expression in MPM tumours and healthy controls, as well as the expression and secretion from cell lines and xenografts.

Results:

Secreted protein acidic and rich in cysteine was identified as a putative prognostic marker in plasma. Validation in the Dutch series showed that the median survival was higher in patients with low SPARC compared with those with high SPARC (19.0 vs 8.8 months; P=0.01). In multivariate analyses, serum SPARC remained as an independent predictor (HR 1.55; P=0.05). In MPM tumour samples, SPARC was present in the tumour cells and stromal fibroblasts. Cellular SPARC expression was higher in 5 out of 7 cell lines compared with two immortalized mesothelial lines. Neither cell lines nor xenograft tumours secreted detectable SPARC.

Conclusions:

Low circulating SPARC was associated with favourable prognosis. Secreted protein acidic and rich in cysteine was present in both tumour cells and stromal fibroblasts; and our in vitro and in vivo experiments suggest that stromal fibroblasts are a potential source of circulating SPARC.     

Expression of secreted protein acidic and rich in cysteine (SPARC) in breast cancer and response to neoadjuvant chemotherapy

BackgroundSecreted protein acidic and rich in cysteine (SPARC) has been suggested as a new biomarker and therapeutic target in breast cancer, as well as other tumor types.Patients and methodsWe evaluated the frequency of SPARC expression among different molecular breast cancer subtypes and its role for therapy response after neoadjuvant chemotherapy. In this study, pretherapeutic core biopsies of 667 patients from the neoadjuvant GeparTrio trial were evaluated for SPARC expression by immunohistochemistry using a standardized immunoreactive score (IRS).ResultsAn increased SPARC expression (IRS ≥6) was observed in 26% of all tumors. In triple-negative tumors, SPARC expression was increased in 37% of tumors, compared with other molecular subtypes (23% HR+/HER2-, 29% HR+/HER2+ and 22% HR-/HER2+; P = 0.038). Increased SPARC expression was associated with an increased pathological complete response (pCR) rate of 27%, compared with 15% in tumors with low SPARC expression (P < 0.001). In the triple-negative subgroup, pCR rates were 47% in tumors with high SPARC expression, compared with 26% in tumors with low SPARC expression (P = 0.032). In multivariable analysis, SPARC was independently predictive in the overall population (P = 0.010) as well as the triple-negative subgroup (P = 0.036).ConclusionsSPARC is frequently expressed in breast cancer with triple-negative breast cancer revealing the highest expression rate. High SPARC expression of the primary tumor is associated with a higher chance of achieving a pathological complete remission after TAC or TAC-NX chemotherapy. As SPARC is an albumin-binding protein and might mediate intratumoral accumulation of albumin bound drugs, SPARC should be further evaluated as a predictive marker especially for response to albumin-bound drugs like nab-paclitaxel.Clinical trial numberNCT00544765.     

Immunohistochemical expression of excision repair cross-complementing 1 (ERCC1) in non-small-cell lung cancer: implications for patient outcome

INTRODUCTION The identification of novel prognostic markers may help to better assess survival probability in different subgroups of patients with non-small-cell lung cancer (NSCLC) and to tailor treatment according to the molecular profile of the tumour. AIM We sought to examine whether the immunohistochemical expression of excision repair cross-complementing 1 (ERCC1), an essential component of the nucleotide excision repair pathway, may predict prognosis in NSCLC. MATERIAL AND METHOD Formalin-fixed paraffin-embedded tumour samples from 44 Turkish patients with NSCLC treated by adjuvant platinum-based chemotherapy were included in the study. Immunohistochemical expression levels of ERCC1 were correlated with clinical outcomes by Kaplan-Meier curves and multivariable Cox proportional hazards regression analysis. RESULTS A total of 29 patients had ERCC1-negative tumours while 15 had ERCC1-positive tumours. The mean progression- free survival (PFS) was significantly lower in patients with ERCC1-positive tumours (13±2 months) than in those with ERCC1-negative tumours (27±5 months, p<0.05). Similarly, the mean overall survival (OS) was significantly lower in patients with ERCC1-positive tumours (20±3 months) than in those with ERCC1-negative tumours (33±5 months, p<0.05). After allowance for potential confounders, Cox regression analysis demonstrated that ERCC1 expression was significantly associated with both PFS and OS (both p<0.05). CONCLUSION This study provides support for the prognostic value of ERCC1 immunohistochemical expression in patients with NSCLC treated by adjuvant platinum-based chemotherapy. If independently confirmed, these findings may improve prognostic stratification in this group of patients.     

Secreted protein acidic and rich in cysteine inhibits the growth of human pancreatic cancer cells with G1 arrest induction

Aberrant secreted protein acidic and rich in cysteine (SPARC) expression has been reported to play an important role in the tumor development. However, the pattern and the role of SPARC in pancreatic cancer remain largely unknown. Therefore, we further deciphered the role of SPARC played in pancreatic cancer. We first evaluated the SPARC expression in human pancreatic cancer tissues and pancreatic cancer cells. Then we forced expression and silenced SPARC expression in pancreatic cancer cell lines MIA PaCa2 and PANC-1, respectively, using lentivirus vectors. We characterized the stable cells in vitro. In this study, we found that SPARC expression was weak in cancer cells in specimens which negatively correlated with the expression level of phosphorylated pRB and poorer outcome. Moreover, our results demonstrated that SPARC negatively regulated pancreatic cell growth in vitro. Furthermore, we disclosed that the activation of p53 and p27^Kip1 may involve in the effect of SPARC on pancreatic cancer cells. SPARC is downregulated in pancreatic cancer cells and retards the growth of pancreatic cancer cell. Taken together, these results indicate SPARC may be a potential target for pancreatic cancer therapy.     

核苷酸还原酶亚单位M1和内切修复交叉补体1在非小细胞肺癌中的研究进展

核苷酸还原酶亚单位M1（RRM1）属抑癌基因，RRM1可以激发G2期检测点功能，使受损的DNA得以修复或者发生凋亡，并具有抑制细胞侵袭和转移的作用，另外RRM1还可以调节核苷酸还原酶的活性，是抗代谢药吉西他滨作用的靶分子，RRM1高表达的细胞对吉西他滨耐药。内切修复交叉补体1（ERCC1）是细胞内负责修复受损DNA的核苷酸内切修复通路中的限速酶，可以识别和去除铂-DNA附加物而导致细胞对铂类耐药。本文综述RRM1和ERCC1在非小细胞肺癌患者预后和化疗个体化方面的研究进展。     

SPARC蛋白在胃癌中的表达及与胃癌预后的关系

目的 探讨富含半胱氨酸(Cys)的酸性分泌蛋白(SPARC蛋白)在胃腺癌组织中的表达及与胃腺癌患者预后的关系。方法 免疫组化法检测104例胃腺癌组织和30例癌旁组织中SPARC蛋白的表达差异,并应用统计学的方法分析SPARC蛋白与胃腺癌患者预后的关系。结果 SPARC蛋白在30例癌旁胃黏膜组织中阳性率为20%(6/30),且均为弱表达或无表达,在104例胃腺癌组织中阳性率为76.1%(79/104),二者差异有统计学意义(P＜0.01)。胃腺癌组织中,SPARC蛋白表达高低与淋巴结转移及组织分化程度呈正相关(P＜0.05);SPARC蛋白高表达的胃腺癌患者平均生存时间为27.4个月,明显低于低表达者的40.9个月(P＜0.05)。结论 SPARC蛋白在胃腺癌组织中高表达,且主要表达于胃腺癌细胞周围的间质中;其与淋巴结转移及组织分化程度显著相关;SPARC蛋白高表达的胃腺癌患者生存期短,预后差,但SPARC蛋白不是其独立的预后因素。     

Highly sensitive detection of melanoma at an early stage based on the increased serum secreted protein acidic and rich in cysteine and glypican-3 levels.

PURPOSE: There are no available tumor markers detecting primary melanoma at an early stage. The identification of such serum markers would be of significant benefit for an early diagnosis of melanoma. We recently identified glypican-3 (GPC3) as a novel tumor marker but could diagnose only 40% of melanomas. Thereby, we focused out attention on secreted protein acidic and rich in cysteine (SPARC) overexpressed in melanoma as another candidate for tumor marker. EXPERIMENTAL DESIGN: Secreted SPARC protein was quantified using ELISA in the sera from 109 melanoma patients, five patients with large congenital melanocytic nevus, 61 age-matched healthy donors, and 13 disease-free patients after undergoing a surgical removal. We also quantified GPC3 and 5-S-cysteinyldopa in the same serum samples and compared these markers for their diagnostic value. RESULTS: The serum SPARC concentrations in melanoma patients were greater than those in healthy donors (P = 0.001). When we fixed a cutoff value at the mean concentration plus 2 SD of the healthy donors, the serum SPARC was found to have increased in the sera of 36 of the 109 (33%) melanoma patients, whereas there were three (4.9%) false-positive cases of 61 healthy donors. Surprisingly, 19 of 36 patients showing increased SPARC levels were in stages 0 to II. The serum SPARC level decreased under the cutoff level in 10 of 13 patients after surgical removal. Using SPARC and GPC3 in combination thus enabled us to diagnose 47 of 75 (66.2%) melanoma patients at an early stage (0-II). CONCLUSIONS: SPARC or its combination with GPC3 is thus considered a potentially useful tumor marker, especially for melanoma at an early stage.     

The C1772T genetic polymorphism in human HIF-1alpha gene associates with expression of HIF-1alpha protein in breast cancer

Hypoxia-inducible factor 1 (HIF-1) is an important genetic component involved in the cellular response to hypoxia. HIF-1 is also linked to the regulation of tumor development and growth. In previous studies, the C1772T (P582S) or the G1790A (A588T) polymorphisms of the HIF-1alpha gene have been identified in renal cell carcinoma, head and neck and esophageal squamous cell carcinomas as well as colorectal and prostate cancers. In our study, we investigated whether polymorphisms of the HIF-1alpha gene may account for the expression patterns of HIF-1alpha protein and impact of clinical progression in breast cancer. We also examined the impact of prognosis of HIF-1alpha gene polymorphism and protein expression in the prediction of biological behavior. We performed polymerase chain reaction and direct sequencing to detect polymorphisms in exon 12 of HIF-1alpha from 90 breast cancer patients and 102 healthy controls. The expression of HIF-1alpha was measured in paraffin-embedded specimens from patients by immunohistochemistry. We associated its expression with known prognostic factors. The frequency of the T allele for C1772T in breast cancer patients and healthy controls was 5.6 vs. 4.4%, whereas, the frequency of the A allele for G1790A was 1.7 vs. 4.4%. HIF-1alpha was overexpressed in 56.7% (51 of 90) of the patients. Its overexpression associated with the T1772 polymorphic allele (p=0.04). Elevated levels of HIF-1alpha protein were found in cases of breast cancer with lymph node metastasis (p=0.041), high histological grade (p=0.001) and increased Ki-67 index (p=0.031). These results suggest the potential use of C1772T (P582S) polymorphism and expression analysis in providing a new prognostic factor for unfavorable disease outcomes and may help for clinical decision-making in the treatment of breast cancer patients.     

Deregulation of base excision repair gene expression and enhanced proliferation in head and neck squamous cell carcinoma

Defects in the DNA damage repair pathway contribute to cancer. The major pathway for oxidative DNA damage repair is base excision repair (BER). Although BER pathway genes (OGG1, APEX1 and XRCC1) have been investigated in a number of cancers, our knowledge on the prognostic significance of these genes and their role in head and neck squamous cell carcinoma is limited. Protein levels of OGG1, APEX1 and XRCC1 and a proliferation marker, Ki-67, were examined by immunohistochemical analysis, in a cohort of 50 HNSCC patients. Significant downregulation of OGG1 (p?<?0.04) and XRCC1 (p?<?0.05) was observed in poorly differentiated HNSCC compared to mod–well-differentiated cases. Significant upregulation of APEX1 (p?<?0.05) and Ki-67 (p?<?0.05) was observed in poorly differentiated HNSCC compared to mod-well-differentiated cases. Significant correlation was observed between XRCC1 and OGG1 (r?=?0.33, p?<?0.02). Inverse correlations were observed between OGG1 and Ki-67 (r?=??0.377, p?<?0.005), between APEX1 and XRCC1 (r?=??0.435, p?<?0.002) and between OGG1 and APEX1 (r?=??0.34, p?<?0.02) in HNSCC. To confirm our observations, we examined BER pathway genes and a proliferation marker, Ki-67, expression at the mRNA level on 50 head and neck squamous cell carcinoma (HNSCC) and 50 normal control samples by quantitative real-time polymerase chain reaction. Significant downregulation was observed in case of OGG1 (p?<?0.04) and XRCC1 (p?<?0.02), while significant upregulation was observed in case of APEX1 (p?<?0.01) and Ki-67 (p?<?0.03) in HNSCC tissue samples compared to controls. Our data suggested that deregulation of base excision repair pathway genes, such as OGG1, APEX1 and XRCC1, combined with overexpression of Ki-67, a marker for excessive proliferation, may contribute to progression of HNSCC in Pakistani population.     

Comparison of DNA repair protein expression and activities between human fibroblast cell lines with different radiosensitivities

In order to investigate the molecular basis of variation in response to ionising radiation (IR) in radiotherapy patients, we have studied the expression of several genes involved in DNA double-strand break repair pathways in fibroblast cell lines. Ten lines were established from skin biopsies of cancer patients with different normal-tissue reactions to IR, and 3 from a control individual. For all 10 test cell lines, the cellular radiosensitivity was also known. Using Western blots we measured, in non-irradiated cells, the basal expression levels of ATM, Rad1 and Hus1, involved in the control of cellular DNA damage checkpoints, together with DNA-PKcs, Ku70, Ku80; XRCC4, ligaseIV and Rad51, involved in radiation- induced DSB repair. We also analysed the in vitro enzymatic activities, under non-irradiated conditions, of the DNA-PK and XRCC4/ligaseIV complexes. The levels of expression of the different proteins were similar in all the cell lines, but the activities of the DNA-PK and XRCC4/ligaseIV complexes showed some differences. These differences did not correlate with either the normal tissue response of the patient in vivo or with cellular radiation sensitivity in vitro. The activity differences of these enzyme complexes, therefore, do not account for the variation of responses seen between patients.     

Impacts of excision repair cross-complementing gene 1 (ERCC1), dihydropyrimidine dehydrogenase, and epidermal growth factor receptor on the outcomes of patients with advanced gastric cancer

Using laser-captured microdissection and a real-time RT-PCR assay, we quantitatively evaluated mRNA levels of the following biomarkers in paraffin-embedded gastric cancer (GC) specimens obtained by surgical resection or biopsy: excision repair cross-complementing gene 1 (ERCC1), dihydropyrimidine dehydrogenase (DPD), methylenetetrahydrofolate reductase (MTHFR), epidermal growth factor receptor (EGFR), and five other biomarkers related to anticancer drug sensitivity. The study group comprised 140 patients who received first-line chemotherapy for advanced GC. All cancer specimens were obtained before chemotherapy. In patients who received first-line S-1 monotherapy (69 patients), low MTHFR expression correlated with a higher response rate (low: 44.9% vs high: 6.3%; P=0.006). In patients given first-line cisplatin-based regimens (combined with S-1 or irinotecan) (43 patients), low ERCC1 correlated with a higher response rate (low: 55.6% vs high: 18.8%; P=0.008). Multivariate survival analysis of all patients demonstrated that high ERCC1 (hazard ratio (HR): 2.38 (95% CI: 1.55-3.67)), high DPD (HR: 2.04 (1.37-3.02)), low EGFR (HR: 0.34 (0.20-0.56)), and an elevated serum alkaline phosphatase level (HR: 1.00 (1.001-1.002)) were significant predictors of poor survival. Our results suggest that these biomarkers are useful predictors of clinical outcomes in patients with advanced GC.     

乳腺导管内乳头状瘤及其癌变组织CD44v6蛋白表达的研究

背景与目的：CD44v6是乳腺上皮恶性转化中的一个重要成分,在乳腺良恶性病变中有不同的表达,但其在良恶性病变的鉴别诊断中的价值并没有得到很好和研究,本研究目的是检测CD44v6在乳腺导管内乳头状瘤及导管内乳头状瘤癌变组织中的表达,探讨CD44v6在乳腺导管内乳头状瘤诊断及鉴别诊断中的作用。方法：对49例导管内乳头状瘤,12例导管内乳头状瘤癌变,15例导管内癌,15例浸润性导管癌及20例正常乳腺组织的石蜡切片进行免疫组织化学染色。结果：在正常组织,导管内乳头状瘤,乳头状瘤癌变,导管内癌,浸润性导管癌中,肌上皮细胞（basal epithelial cell)的CD44v6蛋白表达阳性（＋＋／＋＋＋）率分别为95．00％,85。72％,66。66％,66。66％,0％,导管内乳头状瘤与乳头状瘤癌变之间无统计学差异（P＞0．05）,而上此细胞（luminal epithelial cell)的CD44v6蛋白表达阳性（＋＋／＋＋＋）率分别为5．00％,83．34％,93．33％,100％,导管内乳头状瘤与乳头状瘤癌变之间有统计学差异（P＜0．01）,结论：通过免疫组化检测CD44v6蛋白表达对诊断导管内乳头状瘤是否癌变具有重要参考价值。     

Impact of excision repair cross-complementing gene 1 (ERCC1) on the outcomes of patients with advanced gastric cancer: correlative study in Japan Clinical Oncology Group Trial JCOG9912

BackgroundSince the best chemotherapy regimen for each patient with advanced gastric cancer is uncertain, we aimed to identify molecular prognostic or predictive biomarkers from biopsy specimens in JCOG9912, a randomized phase III trial for advanced gastric cancer.Patients and methodsEndoscopic biopsy specimens from primary lesions were collected in 445 of 704 randomized patients in JCOG9912. We measured the mRNA expression of excision repair cross-complementing group 1 (ERCC1), thymidylate synthase, dihydropyrimidine dehydrogenase, and five other genes, then, categorized them into low and high groups relative to the median, and examined whether gene expression was associated with efficacy end point.ResultsMultivariate analyses showed that high ERCC1 expression [HR 1.37; 95% confidence interval (CI) 1.08–1.75; P = 0.010], performance status ≥1 (HR 1.45; 95% CI 1.13–1.86; P = 0.004), and number of metastatic sites ≥2 (HR 1.66; 95% CI 1.28–1.86; P < 0.001) were associated with a poor prognosis, and recurrent disease (versus unresectable; HR 0.75; 95% CI 0.56–1.00; P = 0.049) was associated with a favorable prognosis. None of these molecular factors were a predictive marker for choosing irinotecan plus cisplatin or 5-fluorouracil rather than S-1.ConclusionThese correlative analyses suggest that ERCC1 is an independent prognostic factor for overall survival in the first-line treatment of gastric cancer.Clinical Trial NumberC000000062, www.umin.ac.jp.     

The expression of thymidylate synthase (TS) and excision repair complementing-1 (ERCC-1) protein in patients with unresectable colorectal cancer treated with mFOLFOX6 therapy

Thymidylate synthase (TS) and excision repair complementing-1 (ERCC-1) were known to be important biomarkers to predict a tumor response to 5-fluorouracil (5-FU) and oxaliplatin, but the relationship between these expressions and tumor response were still unclear. The aim of this study was to determine whether the expression of TS and ERCC-1 protein predict a tumor response in patients with unresectable colorectal cancer treated with mFOLFOX6 therapy as first-line treatment. Fifty patients with unresectable colorectal cancer treated with mFOLFOX6 therapy were enrolled in this study. The expression of TS and ERCC-1 protein in primary cancer cells were examined using immunohistochemistry. There were no significant differences between response rate and the expression of TS or ERCC-1 protein (TS: p>0.99, ERCC-1: p= 0.50). There were no significant differences between progression-free survival time and the expression of TS or ERCC-1 protein (TS: p=0.60, ERCC-1: p=0.60). In this study, the expression TS and ERCC-1 protein may not be useful for the prediction of tumor response in patients with unresectable colorectal cancer treated with mFOLFOX6 therapy.     

Reduced expression of DNA repair genes and chemosensitivity in 1p19q codeleted lower-grade gliomas

Background

Lower-grade gliomas (LGGs, defined as WHO grades II and III) with 1p19q codeletion have increased chemosensitivity when compared to LGGs without 1p19q codeletion, but the mechanism is currently unknown.

Methods

RNAseq data from 515 LGG patients in the Cancer Genome Atlas (TCGA) were analyzed to compare the effect of expression of the 9 DNA repair genes located on chromosome arms 1p and 19q on progression free survival (PFS) and overall survival (OS) between patients who received chemotherapy and those who did not. Chemosensitivity of cells with DNA repair genes knocked down was tested using MTS cell proliferation assay in HS683 cell line and U251 cell line.

Results

The expression of 9 DNA repair genes on 1p and 19q was significantly lower in 1p19q-codeleted tumors (n?=?175) than in tumors without the codeletion (n?=?337) (p?<?0.001). In LGG patients who received chemotherapy, lower expression of LIG1, POLD1, PNKP, RAD54L and MUTYH was associated with longer PFS and OS. This difference between chemotherapy and non-chemotherapy groups in the association of gene expression with survival was not observed in non-DNA repair genes located on chromosome arms 1p and 19q. MTS assays showed that knockdown of DNA repair genes LIG1, POLD1, PNKP, RAD54L and MUTYH significantly inhibited recovery in response to temozolomide when compared with control group (p?<?0.001).

Conclusions

Our results suggest that reduced expression of DNA repair genes on chromosome arms 1p and 19q may account for the increased chemosensitivity of LGGs with 1p19q codeletion.