Binbin Cui

The lncRNA CRNDE promotes colorectal cancer cell proliferation and chemoresistance via miR-181a-5p-mediated regulation of Wnt/β-catenin signaling

BackgroundWith more than 600,000 mortalities each year, colorectal cancer (CRC) is the third most commonly diagnosed type of cancer worldwide. Recently, mechanisms involving noncoding RNAs have been implicated in the development of CRC.MethodsWe examined expression levels of lncRNA CRNDE and miR-181a-5p in 64 cases of CRC tissues and cell lines by qRT-PCR. Gain-of-function and loss-of-function assays were performed to examine the effect of CRNDE and miR-181a-5p on proliferation and chemoresistance of CRC cells. Using fluorescence reporter and western blot assays, we also explored the possible mechanisms of CRNDE in CRC cells.ResultsIn this study, we found that the expression levels of the CRNDE were upregulated in CRC clinical tissue samples. We identified microRNA miR-181a-5p as an inhibitory target of CRNDE. Both CRNDE knockdown and miR-181a-5p overexpression in CRC cell lines led to inhibited cell proliferation and reduced chemoresistance. We also determined that β-catenin and TCF4 were inhibitory targets of miR-181a-5p, and that Wnt/β-catenin signaling was inhibited by both CRNDE knockdown and miR-181a-5p overexpression. Significantly, we found that the repression of cell proliferation, the reduction of chemoresistance, and the inhibition of Wnt/β-catenin signaling induced by CRNDE knockdown would require the increased expression of miR-181a-5p.ConclusionsOur study demonstrated that the lncRNA CRNDE could regulate the progression and chemoresistance of CRC via modulating the expression levels of miR-181a-5p and the activity of Wnt/β-catenin signaling.

Expression and clinicopathological significance of EED, SUZ12 and EZH2 mRNA in colorectal cancer.

AbstractBackground and objectivesEnhancer of zeste 2 (EZH2), embryonic ectoderm development (EED), and suppressor of zeste 12 homolog (SUZ12), the key component of polycomb repressive complex 2, are of great importance in human cancer pathogenesis. This study was designed to investigate the clinical and prognostic significances of EZH2, EED and SUZ12 in colorectal cancer (CRC) patients.nMethodsThe expression of EZH2, EED and SUZ12 mRNA was evaluated in 82 primary CRC and paired non-cancerous mucosa samples by qRT-PCR.nResultsWe found that overall EZH2, EED and SUZ12 mRNA expression in the CRC tissues was significantly increased than in the non-cancerous tissue (pxa0<xa00.05). Increased EZH2, EED and SUZ12 mRNA expression was directly correlated with primary tumor size, regional lymph node metastases, distant metastasis and AJCC stage. Furthermore, CRC patients with higher level of EED, SUZ12 or EZH2 showed a worse disease-free survival (DFS) (pxa0<xa00.01). In multivariate analysis, the increased EZH2 expression may be a risk factor for the patients’ 3-year DFS (HR 2.517; 95xa0% CI 1.104, 5.736; pxa0=xa00.028). Furthermore, the k-means cluster analysis showed that high mRNA expression of EED, SUZ12 and EZH2 was significantly correlated with the aggressive clinical behavior and poor prognosis.ConclusionsHigh expression of EED, SUZ12 and EZH2 might contribute to the CRC development/progression.

Tuning the entanglement between orbital reconstruction and charge transfer at a film surface

The interplay between orbital, charge, spin, and lattice degrees of freedom is at the core of correlated oxides. This is extensively studied at the interface of heterostructures constituted of two-layer or multilayer oxide films. Here, we demonstrate the interactions between orbital reconstruction and charge transfer in the surface regime of ultrathin (La,Sr)MnO3, which is a model system of correlated oxides. The interactions are manipulated in a quantitative manner by surface symmetry-breaking and epitaxial strain, both tensile and compressive. The established charge transfer, accompanied by the formation of oxygen vacancies, provides a conceptually novel vision for the long-term problem of manganites—the severe surface/interface magnetization and conductivity deterioration. The oxygen vacancies are then purposefully tuned by cooling oxygen pressure, markedly improving the performances of differently strained films. Our findings offer a broad opportunity to tailor and benefit from the entanglements between orbit, charge, spin, and lattice at the surface of oxide films.

Association between co-inhibitory molecule gene tagging single nucleotide polymorphisms and the risk of colorectal cancer in Chinese.

AbstractPurposenT lymphocyte immune responses are controlled by both co-stimulatory and co-inhibitory signaling through T cell co-receptors. Cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death 1 (PD-1) and B and T lymphocyte attenuator (BTLA) are all co-inhibitory molecules that negatively regulate the activation of T cells. In this study, we investigated the relationship between ten tagging SNPs in three co-inhibitory molecule genes and colorectal cancer (CRC).MethodsWe conducted a hospital-based case–control study consisting of 601 cases with CRC and 627 CRC-free individuals from the Heilongjiang Province of China.ResultsThe rs7421861 CT genotype was significantly associated with the risk of colorectal cancer compared to the wild-type TT genotype (adjusted OR 1.314, 95xa0% CI 1.012–1.706, Pxa0=xa00.041). The rs2705535 TT genotype was associated with the risk of rectal cancer [OR 1.819 (1.093–3.027), Pxa0=xa00.021]. There was statistical interaction between the PD-1/rs2227982 (CTxa0+xa0TT) genotypes and high seafood intake (>once/week), as well as the CTLA-4/rs231777 variant and high pungent food intake (>3xa0times/week). The AGxa0+xa0AA genotypes of CTLA-4/rs3087243 statistically and antagonistically interacted with soybeans, pork and alcohol intake and were associated with CRC risk. Analogously, BTLA/rs1844089 interacted with pork intake, PD-1/rs7421861 with beef and lamb consumption and PD-1/rs6710479 with barbecue consumption. Haplotype G-C-G-A-T-T-A was significantly associated with CRC risk (OR 1.221 Pxa0=xa00.034).ConclusionsThese data indicate potential associations between BTLA and PD-1 polymorphisms and CRC susceptibility. Additionally, the three co-inhibitory molecule gene SNPs have environmental interactions associated with CRC risk.

The learning curve for the laparoscopic approach for colorectal cancer: a single institution's experience.

BACKGROUNDnThe purpose of this study was to evaluate the learning curve of the laparoscopic approach for colorectal cancer and generate a focused training program for more junior surgeons.nnnSUBJECTS AND METHODSnThis study analyzed data from 100 consecutive laparoscopic surgeries for colorectal cancer between January 2009 and July 2010. The learning curve was compared between the first 50 surgeries (study group 1) and the subsequent 50 surgeries (study group 2).nnnRESULTSnAge, gender, mean body mass index, history of abdominal surgery, and tumor stage were not significantly different between the two study groups. Operative time decreased with increasing experience and reached a plateau after 23 patients. The operative time in study group 2 tended to be shorter than in study group 1 (P=.06). Other parameters including blood loss, average number of retrieved lymph nodes, conversion rate, and intraoperative complication rates were not different between the two study groups.nnnCONCLUSIONSnMore junior surgeons can be safely trained if they are exposed to a focused training program. Supervision by an experienced surgeon and considerable experiences in open colorectal surgery are assets for an accelerated learning curve.

Novel irreversible EGFR tyrosine kinase inhibitor 324674 sensitizes human colon carcinoma HT29 and SW480 cells to apoptosis by blocking the EGFR pathway

BACKGROUNDnEpidermal growth factor receptor (EGFR) is widely expressed in multiple solid tumors including colorectal cancer by promoting cancer cell growth and proliferation. Therefore, the inhibition of EGFR activity may establish a clinical strategy of cancer therapy.nnnMETHODSnIn this study, using human colon adenocarcinoma HT29 and SW480 cells as research models, we compared the efficacy of four EGFR inhibitors in of EGFR-mediated pathways, including the novel irreversible inhibitor 324674, conventional reversible inhibitor AG1478, dual EGFR/HER2 inhibitor GW583340 and the pan-EGFR/ErbB2/ErbB4 inhibitor. Cell proliferation was assessed by MTT analysis, and apoptosis was evaluated by the Annexin-V binding assay. EGFR and its downstream signaling effectors were examined by western blotting analysis.nnnRESULTSnAmong the four inhibitors, the irreversible EGFR inhibitor 324674 was more potent at inhibiting HT29 and SW480 cell proliferation and was able to efficiently induce apoptosis at lower concentrations. Western blotting analysis revealed that AG1478, GW583340 and pan-EGFR/ErbB2/ErbB4 inhibitors failed to suppress EGFR activation as well as the downstream mitogen-activated protein kinase (MAPK) and PI3K/AKT/mTOR (AKT) pathways. In contrast, 324674 inhibited EGFR activation and the downstream AKT signaling pathway in a dose-dependent manner.nnnCONCLUSIONnOur studies indicated that the novel irreversible EGFR inhibitor 324674 may have a therapeutic application in colon cancer therapy.

Small interfering RNA targeting Rac1 sensitizes colon cancer to dihydroartemisinin-induced cell cycle arrest and inhibited cell migration by suppressing NFκB activity

Dihydroartemisinin (DHA) has recently shown antitumor activity in various cancer cells. The small GTPase Rac1 regulates many cellular processes, including cytoskeletal reorganization, cell migration, proliferation, and survival. In addition, Rac1 plays a major role in activating NFκB-mediated transcription. Both Rac1 and NFκB regulate many properties of the malignant phenotype, including anchorage-independent proliferation and survival, metastasis, and angiogenesis. In this study, for the first time, we demonstrated that Rac1 knockdown can enhance DHA-induced growth inhibition, cell cycle arrest, apoptosis, and migration in both HCT116 and RKO cell lines in vitro. The mechanism is due partially to DHA, and Rac1 siRNA deactivates NFκB activity, so as to decrease tremendously the expression of its target gene products, such as PCNA, cyclin D1, and CDK4; and increase the expression of p21, cleaved-caspase-3, and cleaved-PARP. In our in vivo studies, DHA also manifested remarkably enhanced antitumor effect when combined with Rac1 siRNA. We concluded that inhibition of NFκB activation is one of the mechanisms that Rac1 siRNA dramatically promotes DHAs antitumor effect on human colon cancer.

Identification of spliced variants of the proto-oncogene hdm2 in colorectal cancer†‡

The human double minute 2 (hdm2) oncogene is a negative regulator of the p53 gene. Expression and alternative splicing of the hdm2 gene may contribute to colorectal cancer development or progression. This study aimed to determine the presence and identification of aberrant mRNA transcripts of hdm2 in colorectal cancer tissues and cell lines, and determine the nature of their association with clinicopathological characteristics and survival of patients.

Methylation of a panel of genes in peripheral blood leukocytes is associated with colorectal cancer

The relationship between the DNA methylation status of the CpG islands of multiple genes in blood leukocytes in CRC susceptibility and prognosis, as well as possible interactions with dietary factors on CRC risk are unclear. We carried out a case-control study including 421 CRC patients and 506 controls to examine the associations between six genes (AOX-1, RARB2, RERG, ADAMTS9, IRF4, and FOXE-1), multiple CpG site methylation (MCSM) and susceptibility to CRC. High-level MCSM (MCSM-H) was defined as methylation of greater than or equal to 2 of 5 candidate genes (except for RARB2); low-level MCSM (MCSM-L) was when 1 candidate gene was methylated; non-MCSM was when none of the candidate genes were methylated. Blood cell-derived DNA methylation status was detected using methylation-sensitive high-resolution melting analysis. The hypermethylation status of each individual gene was statistically significantly associated with CRC. MCSM status was also associated with CRC (ORu2009=u20091.54, 95% CI: 1.15–2.05, Pu2009=u20090.004). We observed interactions between a high level of dietary intake of cereals, pungent food, and stewed fish with brown sauce, age (older than 60 yrs), smoking and hypermethylation on risk of CRC. MCSM in peripheral blood DNA may be an important biomarker for susceptibility to CRC.

Tilt engineering of exchange coupling at G-type SrMnO3/(La,Sr)MnO3 interfaces

With the recent realization of hybrid improper ferroelectricity and room-temperature multiferroic by tilt engineering, “functional” octahedral tilting has become a novel concept in multifunctional perovskite oxides, showing great potential for property manipulation and device design. However, the control of magnetism by octahedral tilting has remained a challenging issue. Here a qualitative and quantitative tilt engineering of exchange coupling, one of the magnetic properties, is demonstrated at compensated G-type antiferromagnetic/ferromagnetic (SrMnO3/La2/3Sr1/3MnO3) interfaces. According to interfacial Hamiltonian, exchange bias (EB) in this system originates from an in-plane antiphase rotation (a−) in G-type antiferromagnetic layer. Based on first-principles calculation, tilt patterns in SrMnO3 are artificially designed in experiment with different epitaxial strain and a much stronger EB is attained in the tensile heterostructure than the compressive counterpart. By controlling the magnitude of octahedral tilting, the manipulation of exchange coupling is even performed in a quantitative manner, as expected in the theoretical estimation. This work realized the combination of tilt engineering and exchange coupling, which might be significant for the development of multifunctional materials and antiferromagnetic spintronics.