Kaiwu Xu

miR-7 inhibits colorectal cancer cell proliferation and induces apoptosis by targeting XRCC2

Background Analysis using publicly available algorithms predicts that X-ray repair complementing defective repair in Chinese hamster cells 2 (XRCC2), a key component in the homologous recombination repair pathway, is a potential target of micro-ribonucleic acid-7 (miR-7). Some studies have shown that both miR-7 and XRCC2 are associated with cancer development. For this purpose, we searched for the possible relationship between miR-7 and XRCC2 in the development of colorectal cancer (CRC). Methods miR-7 expression was assessed in CRC specimens and cell lines using real-time polymerase chain reaction (PCR). Luciferase reporter assay was used to confirm the target associations. The effect of miR-7 on cell proliferation and apoptosis was confirmed in vitro by the methylthiazol tetrazolium (MTT) assay, colony formation assay, and flow cytometry. Gene and protein expression were examined using real time PCR and western blotting, respectively. Results miR-7 was downregulated in CRC specimens and cell lines, and targeted the 3′ untranslated region of XRCC2. miR-7 overexpression reduced cyclin D1 expression and increased p21, caspase-3, and BAX expression, which subsequently inhibited CRC cell proliferation and induced CRC cell apoptosis. However, XRCC2 can repress the inhibitory effects of miR-7 on proliferation. Conclusion Our findings suggest that miR-7 plays a protective role by inhibiting proliferation and increasing apoptosis of CRC cells. It may identify new targets for anti-cancer treatment.

Pancreaticogastrostomy versus pancreaticojejunostomy after pancreaticoduodenectomy: A meta-analysis of randomized control trials

BACKGROUND Postoperative pancreatic fistula (PF) is the leading morbidity after pancreaticoduodenectomy (PD). The pancreatoenteric anastomosis method after PD is associated with the occurrence of PF. Evidence shows that pancreaticogastrostomy (PG) is possibly superior to pancreaticojejunostomy (PJ) in reducing the incidence of PF after PD; however, this remains to be definitively confirmed. METHODS Randomized clinical trials (RCTs) comparing the outcomes of PG versus PJ after PD were retrieved for meta-analysis. RESULTS After a thorough search of the English literature published until March 23rd, 2014, we identified seven RCTs involving 1095 patients (PG group, 548; PJ group, 547) for final analysis. Meta-analysis revealed that the incidence of PF was significantly lower in the PG group (15.7%) than in the PJ group (23.0%, 126/547; OR = 0.61, 95% CI: 0.45-0.83, P = 0.002). Furthermore, the incidence of intra-abdominal fluid collection was also lower in the PG group than in the PJ group (OR = 0.43, 95% CI: 0.28-0.65, P < 0.0001). No significant differences were found between the PG and PJ groups in terms of delayed gastric emptying, hemorrhage, overall morbidity and mortality. CONCLUSIONS PG seemed to be superior to PJ in reducing the incidence of PF and intra-abdominal fluid collection after PD.

Does Preoperative Radio(chemo)therapy Increase Anastomotic Leakage in Rectal Cancer Surgery? A Meta-Analysis of Randomized Controlled Trials

Objective. Preoperative radio(chemo)therapy (pR(C)T) appears to increase postoperative complications of rectal cancer resection, but clinical trials have reported conflicting results. The objective of this meta-analysis was performed to assess the effects of pR(C)T on anastomotic leak after rectal cancer resection. Methods. PubMed, Embase, and the Cochrane Library were searched from January 1980 to January 2014. Randomized controlled trials included all original articles reporting anastomotic leak in patients with rectal cancer, among whom some received preoperative radiotherapy or chemoradiotherapy while others did not. The analysed end-points were the anastomotic leak. Result. Seven randomized controlled trials with 3375 patients were included in the meta-analysis. 1660 forming the group undergoing preoperative radiotherapy or chemoradiotherapy versus 1715 patients undergoing without preoperative radiotherapy or chemoradiotherapy. The meta-analyses found that pR(C)T was not an independent risk factor for anastomotic leakage (OR 1.02, 95% CI 0.80–1.30; P = 0.88). Subgroups analysis was performed and the result was not altered. Conclusions. Current evidence demonstrates that pR(C)T did not increase the risk of postoperative anastomotic leak after rectal cancer resection in patients.

Combined olaparib and oxaliplatin inhibits tumor proliferation and induces G2/M arrest and γ-H2AX foci formation in colorectal cancer

Background Poly (ADP-ribose) polymerase 1 (PARP1) has an important role in homologous recombination repair. The purpose of this study was to investigate the effect of PARP1 inhibitor on oxaliplatin treatment for colorectal cancer (CRC). Methods A cell counting kit-8 assay was used to determine the sensitivity of CRC cells to olaparib and/or oxaliplatin. The gene and protein expressions of PARP1 and the gamma histone variant H2AX (γH2AX) were measured by real-time quantitative polymerase chain reaction and western blotting, respectively. The γH2AX foci formation assay was used to investigate the influence of treatments on cells. Flow cytometry was used to examine the changes in cell cycle distribution. Finally, we investigated the combination of olaparib and oxaliplatin in the CRC tumor model. Results Olaparib changed the expression of γH2AX and PARP1, and increased the sensitivity of CRC cells to oxaliplatin. The γH2AX foci assay showed that olaparib did not induce double-strand breaks (DSBs) alone, but it enhanced the induction of DSBs by oxaliplatin. The flow cytometry results showed that cells exposed to combination treatment had more G2/M-phase cells than control. Additionally, tumor xenograft studies suggested that combined treatment inhibited the growth of CRC. Conclusion CRC cells are sensitized to combined treatment with olaparib and oxaliplatin, and this could be a promising strategy for clinical chemotherapy in CRC.

XRCC2 Promotes Colorectal Cancer Cell Growth, Regulates Cell Cycle Progression, and Apoptosis

AbstractX-ray repair complementing defective repair in Chinese hamster cells 2 (XRCC2) and poly(ADP-ribose) polymerase 1 (PARP1) both play important roles in homologous recombination DNA repair. According to the theory of synthetic lethality, XRCC2-deficient cells are more sensitive to PARP1 inhibitors compared to XRCC2-expressing cells. We investigated XRCC2 expression and function in colorectal cancer (CRC), and the characteristics of sensitivity to PARP1 inhibitor in CRC cells with different XRCC2 levels.We enrolled 153 patients with CRC who had undergone surgery in this study. XRCC2 expression was assessed using immunohistochemistry. Stable CRC SW480 cell lines with low or high XRCC2 expression were constructed. Following treatment with the PARP1 inhibitor olaparib, the viability of cells with different XRCC2 levels was determined; cell cycle distribution and apoptosis were analyzed using flow cytometry. B-cell lymphoma-2 (Bcl-2) protein expression was measured by Western blotting.The positive rates of XRCC2 in primary CRC tissue were significantly higher than that in the matched adjacent noncancerous tissue, and XRCC2 expression status in primary CRC was related to tumor site, Dukes’ stage, and tumor-nodes-metastasis (TNM) stage. XRCC2 overexpression inhibited CRC cell apoptosis and promoted proliferation by enriching cells in the G0/G1 phase. Moreover, olaparib suppressed proliferation, and olaparib sensitivity in CRC cells with high XRCC2 expression was greater.High XRCC2 expression promotes CRC cell proliferation and enriches cells in the G0/G1 phase but inhibits apoptosis. High XRCC2 expression cells are more sensitive to olaparib, which inhibits their viability.

XRCC2 as a predictive biomarker for radioresistance in locally advanced rectal cancer patients undergoing preoperative radiotherapy

XRCC2 has been shown to increase the radioresistance of some cancers. Here, XRCC2 expression was investigated as a predictor of preoperative radiotherapy (PRT) treatment response in locally advanced rectal cancer (LARC). XRCC2 was found to be overexpressed in rectal cancer tissues resected from patients who underwent surgery without PRT. In addition, overall survival for LARC patients was improved in XRCC2-negative patients compared with XRCC2-positive patients after treatment with PRT (P < 0.001). XRCC2 expression was also associated with an increase in LARC radioresistance. Conversely, XRCC2-deficient cancer cells were more sensitive to irradiation in vitro, and a higher proportion of these cells underwent cell death induced by G2/M phase arrest and apoptosis. When XRCC2 was knocked down, the repair of DNA double-strand breaks caused by irradiation was impaired. Therefore, XRCC2 may increases LARC radioresistance by repairing DNA double-strand breaks and preventing cancer cell apoptosis. Moreover, the present data suggest that XRCC2 is a useful predictive biomarker of PRT treatment response in LARC patients. Thus, inhibition of XRCC2 expression or activity represents a potential therapeutic strategy for improving PRT response in LARC patients.

XRCC2 rs3218536 polymorphism decreases the sensitivity of colorectal cancer cells to poly(ADP‑ribose) polymerase 1 inhibitor

Single nucleotide polymorphisms (SNPs) are associated with the development of certain types of cancer. The present study aimed to investigate the association between X-ray repair complementing defective repair in Chinese hamster cells 2 (XRCC2) SNPs and colorectal cancer (CRC) cell sensitivity to the poly(ADP-ribose) polymerase (PARP) 1 inhibitor olaparib (AZD2281). SNaPshot® analysis of XRCC2 SNPs was performed in five CRC cell lines. The AZD2281-sensitivities of the CRC cells were also analyzed using MTT assays. The effect of AZD2281 on XRCC2 and PARP1 expression was investigated in the five cell lines using quantitative polymerase chain reaction and western blot analyses. Parallel investigations were performed using a cisplatin (DDP) model of DNA damage. The XRCC2 rs3218536 SNP was found to be associated with the LoVo microsatellite instability CRC cell line. The relative rate of growth inhibition was found to be lower in the LoVo cells following treatment with AZD2281 compared with the other four cell lines (P=0.002). Furthermore, the XRCC2 mRNA level in the LoVo cells was observed to be significantly higher than that in the other four cell lines (P<0.05). Similar results were found using the DDP model of DNA damage (P<0.05). The present study indicated that the XRCC2 rs3218536 polymorphism decreases the sensitivity of CRC cells to AZD2281.

High expression of SLC17A9 correlates with poor prognosis in colorectal cancer

Solute carrier family 17 member 9 (SLC17A9) is a member of the family of transmembrane proteins that are involved in the transport of small molecules. The role of SLC17A9 in colorectal cancer (CRC) remains poorly understood. The present study aimed to demonstrate the clinicopathological significance and prognostic role of SLC17A9 in CRC. Here, we firstly analyzed the data from The Cancer Genome Atlas on SLC17A9 expression in CRC data sets and detected SLC17A9 expression level in 8 pairs of fresh CRC tissues and adjacent nontumorous tissues by quantitative real-time reverse-transcription polymerase chain reaction and Western blotting assays. Immunohistochemical staining was used to detect SLC17A9 protein expression in 144 CRC patients in our center. The bioinformatic analysis, Western blotting, and immunohistochemical analyses revealed that SLC17A9 was significantly up-regulated in CRC specimens compared with adjacent nontumorous tissues. SLC17A9 overexpression was significantly correlated with several clinicopathological features, such as advanced T stage (P < .001), N stage (P < .001), M stage (P < .001), TNM stage (P < .001), and tumor location (P = .01). A Kaplan-Meier survival curve suggested that higher SLC17A9 expression was statistically correlated with poor overall survival and disease-free survival in patients with CRC. Univariate and multivariate Cox regression analyses demonstrated that SLC17A9 was an independent prognostic predictor for survival of CRC patients. Therefore, our data suggested that SLC17A9 may play an important role in the progression of CRC and may potentially be used as an independent biomarker for prognostic evaluation of CRC.

Tension-free repair during extensive radical surgery for cecal cancer with abdominal wall invasion and inguinal lymph node metastasis.

We report a case of cecal cancer with invasion of the abdominal wall and right inguinal lymph node metastasis. This patient had undergone an appendectomy 2 years previously. He underwent extensive radical right hemicolectomy with anastomosis and tension-free repair of the damaged right lower abdominal wall. The surgery progressed successfully, and the vital signs of the patient were stable (approximately 200 mL blood loss). Postoperative diagnosis revealed moderately to poorly differentiated adenocarcinoma of the cecum with invasion of the abdominal wall and metastasis of the inguinal lymph nodes (pT4bN2bM1, IV4a). The patient has remained well post-surgery.