Multi-omics analyses of glucose metabolic reprogramming in colorectal cancer.

Background: Glucose metabolic reprogramming (GMR) is a cardinal feature of carcinogenesis and metastasis. However, the underlying mechanisms have not been fully elucidated. The aim of this study was to profile the metabolic signature of primary tumor and circulating tumor cells from metastatic colorectal cancer (mCRC) patients using integrated omics analysis. Methods: PET-CT imaging, serum metabolomics, genomics and proteomics data of 325 high 18F-fluorinated deoxyglucose (FDGhigh) mCRC patients were analyzed. The para-tumor, primary tumor and liver metastatic tissues of mCRC patients were used for proteomics analysis. Results: The glucose uptake in tumor tissues as per the PET/CT images was correlated to serum levels of glutamic-pyruvic transaminase (ALT), total bilirubin (TBIL), creatinine (CRE). Proteomics analysis indicated that several differentially expressed proteins were enriched in both GMR and epithelial-mesenchymal transition (EMT)-related pathways. Using a tissue-optimized proteomic workflow, we identified novel proteomic markers (e.g. CCND1, EPCAM, RPS6), a novel PCK1-CDK6-INSR protein axis, and a potential role for FOLR (FR) in GMR/EMT of CRC cells. Finally, CEA/blood glucose (CSR) was defined as a new index, which can be used to jointly diagnose liver metastasis of colorectal cancer. Conclusions: GMR in CRC cells is closely associated with the EMT pathway, and this network is a promising source of potential therapeutic targets.

Copper-Catalyzed Hydrodifluoroalkylation of N-benzylacrylamides via Intramolecular 1,4-Hydrogen Atom Transfer: Reaction Development and Mechanistic Insights.

A one-pot protocol for Cu(I)-catalyzed hydrodifluoroalkylation of benzyl-protected acrylamides to construct difluoropentanedioate compounds in moderate to excellent yields has been achieved by using the benzyl group as a traceless redox-active hydrogen donor. The mechanistic studies confirmed that the reaction proceeds by adding a difluoroalkyl radical to acrylamide, followed by unexpected intramolecular 1,4-hydrogen atom transfer (HAT) and SET oxidation reaction. DFT calculations demonstrate that the destabilizing steric repulsion is the key factor controlling the chemoselectivity, which switches from 1,4-HAT to 5-exo spirocyclization. This work provides an important basis for the 1,4-HAT reaction in theoretical and practical synthesis applications.

Four-dimensional digital subtraction angiography to assess cerebral arteriovenous malformations.

BACKGROUND AND PURPOSE: The performance of a novel prototype four-dimensional (4D) digital subtraction angiography (DSA) for cerebral arteriovenous malformation (AVM) diagnosis was evaluated and compared with that of two-dimensional (2D) and three-dimensional (3D) DSA. METHODS: In this retrospective study, 37 consecutive cerebral AVM patients were included. The standard diagnostic results were concluded from the 2D and 3D DSA. Two 4D DSA volumes were reconstructed for each patient by a commercial and a prototype software, then evaluated by two independent experienced neurosurgeons, who were blinded to the diagnosis and treatment process. The evaluation results were compared with the diagnostic results on Spetzler-Martin (SM) Grading Scale, number of feeding arteries, number of draining veins, and intranidal aneurysms. RESULTS: Complete agreement was achieved between 4D DSA and 2D and 3D DSA in SM Grading Scale and intracranial aneurysm identification (agreement coefficient: 1) for both reviewers. The agreement coefficients were .888 and .917 for both reviewers in feeding artery number determination using 4D DSA product and 4D DSA prototype, respectively. The agreement coefficients in draining vein number determination were all larger than .94 for both reviewers using both 4D DSA volumes. CONCLUSIONS: The performance of this prototype 4D DSA in cerebral AVMs diagnosis was largely equivalent to that of 2D and 3D DSA combination. Four-dimensional DSA can be regarded as a very good complement for 2D DSA in cerebral AVM diagnosis.

Proteomics and liquid biopsy characterization of human EMT-related metastasis in colorectal cancer.

Tumor cells undergo epithelial-mesenchymal transition (EMT), however, there is a room of disagreement in role of EMT heterogeneity to colorectal cancer metastasis (mCRC) evolution. To uncover new EMT-related metastasis proteins and pathways, we addressed the EMT status in colorectal cancer liver metastasis patient-derived CTCs to identify proteins that promote their distant metastasis. And then, we performed a comparative proteomic analysis in matched pairs of primary tumor tissues, adjacent mucosa tissues and liver metastatic tissues. By integrative analysis we show that, unstable Epithelial/Mesenchymal (E/M)-type CTCs had the strongest liver metastases formation ability and the proportion of E/M-type CTCs correlated with distant metastases. Using an optimized proteomic workflow including data independent acquisition (DIA) and parallel reaction monitoring (PRM), we identified novel EMT-related protein cluster (GNG2, COL6A1, COL6A2, DCN, COL6A3, LAMB2, TNXB, CAVIN1) and well-described (ERBB2) core protein level changes in EMT-related metastasis progression, and the proteomic data indicate ERBB2, COL6A1 and CAVIN1 are promising EMT-related metastatic biomarker candidates. This study contributes to our understanding of the role that EMT plays in CRC metastasis and identifies heterogeneous EMT phenotypes as a key piece for tumor progression and prognosis. We further propose that therapies targeting this aggressive subset (E/M-type) of CTCs and related protein may be worthy of exploration as potential suppressors of metastatic evolution.

Evaluation of colorectal cancer liver metastases based on liquid biopsy combined with folate receptor- Positive circulating tumor cells and HSP90.

Objective: Liver metastasis of colorectal cancer (LMCRC) is a major cause of cancer-related deaths worldwide. We can reduce the mortality rate by discerning the risk of liver metastases in patients with colorectal cancer at an early stage. Hence, we combined the use of folate receptor (FR)-labeled circulating tumor cells (FR+CTCs) and the metastasis-related marker, heat shock protein 90 (HSP90), to screen patients with colorectal cancer and explore the prognostic factors of patients with high expression of FR+CTC and HSP90. Patients and methods: A retrospective study of 356 patients with measurable colorectal cancer was performed. Negative enrichment and FR-targeted fluorescence quantitative PCR was utilized to detect FR+CTC. An ELISA kit was used to detect HSP90 expression. A timely follow-up study of patients with colorectal cancer was made. Results: Colorectal patients with liver metastases showed high expression of FR+CTCs and HSP90. The diagnostic ability of the combined receiver operating characteristic curve of FR+CTC and HSP90 (area under the curve [AUC]=0.79, sensitivity 70.55%, specificity 92.66%) was significantly greater than that of a single index. The results of timely follow-up of patients showed that the high expression of FR+CTC significantly shortened the median disease-free survival (mDFS) of 36.5 months (95% confidence interval [CI]: 14.13-58.87, Logrank p < 0.0001) compared with the low expression cohort. The mDFS of the HSP90 high-expression cohort was significantly higher than that of the low-expression cohort (Logrank p = 0.0002), mDFS=58.47 months (95% CI: 37.12-79.81, Logrank p < 0.0001). We performed univariate and multivariate analyses to show that FR+CTC and HSP90 were risk factors for the progression of metastatic colorectal cancer (MCRC) disease. We then constructed a high- and low-risk score model of risk factors to evaluate MCRC. The diagnostic sensitivity of the risk model for MCRC was significantly improved (AUC=0.89, sensitivity 85.29%, specificity 81.33%), and the mDFS of patients in a high-risk group increased to 33.28 months (95% CI: 27.24-39.31, Logrank p < 0.0001). The establishment of the model improves the early screening of patients with MCRC. Conclusion: Patients with colorectal cancer and high expression of FR+CTC and HSP90 are at risk of liver metastasis and this suggests a poor prognosis. Combining the two markers can improve the early screening and diagnosis of LMCRC patients. In addition, combining a multivariate risk model can further assist patients in appropriate stratification and the design of tailored treatment regimens. However, further validation these markers is needed before their routine clinical application.

MTUS1 is a promising diagnostic and prognostic biomarker for colorectal cancer.

BACKGROUND: The morbidity and mortality of colorectal cancer (CRC) remain high, posing a serious threat to human life and health. The early diagnosis and prognostic evaluation of CRC are two major challenges in clinical practice. MTUS1 is considered a tumour suppressor and can play an important role in inhibiting cell proliferation, migration, and tumour growth. Moreover, the expression of MTUS1 is decreased in different human cancers, including CRC. However, the biological functions and molecular mechanisms of MTUS1 in CRC remain unclear. METHODS: In the present study, data from The Cancer Genome Atlas (TCGA) database were analysed using R statistical software (version 3.6.3.) to evaluate the expression of MTUS1 in tumour tissues and adjacent normal tissues using public databases such as the TIMER and Oncomine databases. Then, 38 clinical samples were collected, and qPCR was performed to verify MTUS1 expression. We also investigated the relationship between MTUS1 expression and clinicopathological characteristics and elucidated the diagnostic and prognostic value of MTUS1 in CRC. In addition, the correlation between MTUS1 expression and immune infiltration levels was identified using the TIMER and GEPIA databases. Furthermore, we constructed and analysed a PPI network and coexpression modules of MTUS1 to explore its molecular functions and mechanisms. RESULTS: CRC tissues exhibited lower levels of MTUS1 than normal tissues. The logistic regression analysis indicated that the expression of MTUS1 was associated with N stage, TNM stage, and neoplasm type. Moreover, CRC patients with low MTUS1 expression had poor overall survival (OS). Multivariate analysis revealed that the downregulation of MTUS1 was an independent prognostic factor and was correlated with poor OS in CRC patients. MTUS1 expression had good diagnostic value based on ROC analysis. Furthermore, we identified a group of potential MTUS1-interacting proteins and coexpressed genes. GO and KEGG enrichment analyses showed that MTUS1 was involved in multiple cancer-related signalling pathways. Moreover, the expression of MTUS1 was significantly related to the infiltration levels of multiple cells. Finally, MTUS1 expression was strongly correlated with various immune marker sets. CONCLUSIONS: Our results indicated that MTUS1 is a promising biomarker for predicting the diagnosis and prognosis of CRC patients. MTUS1 can also become a new molecular target for tumour immunotherapy.

Oral-Intestinal Microbiota in Colorectal Cancer: Inflammation and Immunosuppression.

It is widely recognized that microbial disorders are involved in the pathogenesis of many malignant tumors. The oral and intestinal tract are two of the overriding microbial habitats in the human body. Although they are anatomically and physiologically continuous, belonging to the openings at both ends of the digestive tract, the oral and intestinal microbiome do not cross talk with each other due to a variety of reasons, including intestinal microbial colonization resistance and chemical barriers in the upper digestive tract. However, this balance can be upset in certain circumstances, such as disruption of colonization resistance of gut microbes, intestinal inflammation, and disruption of the digestive tract chemical barrier. Evidence is now accruing to suggest that the oral microbiome can colonize the gut, leading to dysregulation of the gut microbes. Furthermore, the oral-gut microbes create an intestinal inflammatory and immunosuppressive microenvironment conducive to tumorigenesis and progression of colorectal cancer (CRC). Here, we review the oral to intestinal microbial transmission and the inflammatory and immunosuppressive microenvironment, induced by oral-gut axis microbes in the gut. A superior comprehension of the contribution of the oral-intestinal microbes to CRC provides new insights into the prevention and treatment of CRC in the future.

OX40 as a novel target for the reversal of immune escape in colorectal cancer.

First-generation immunological checkpoint inhibitors, such as CTLA-4, PD-L1 and PD-1 exhibit significant advantages over conventional cytotoxic drugs, such as oxaliplatin and 5-FU, for the treatment of colorectal cancer. However, these inhibitors are not ideal due to their low objective response rate and the vulnerability of these treatment methods when faced with emerging drug resistant cancers. This study summarizes the immunological characteristics of colorectal cancer treatment, and analyzes the ways in which OX40 may improve the efficacy of these treatments. Activation of the OX40 signaling pathway can enhance the activity of CD4+/CD8+ T cells and inhibit the function of Treg. Simultaneously, OX40 can directly inhibit the expression of Foxp3, affect the inhibitory function of Treg, and inhibit the immunosuppressive factors in the tumor microenvironment so as to reverse immune escape and reverse drug resistance. Therefore, OX40 is an important target for treating colorectal cancer in "cold tumors" with less immunogenicity.

Anlotinib suppresses metastasis and multidrug resistance via dual blockade of MET/ABCB1 in colorectal carcinoma cells.

Anlotinib, a highly selective multi-targeted tyrosine kinase inhibitor (TKI) has therapeutic effects on non-small-cell lung cancer (NSCLC). In this study, the anti-tumor activity and molecular mechanism of anlotinib in metastatic colorectal cancer (mCRC) was explored. The anti-angiogenesis, anti-metastasis, anti-proliferative, and anti-multidrug resistance efficacy of anlotinib were analyzed by using in vitro and in vivo models of human CRC cells. The results indicated that anlotinib boosted chemo-sensitivity of CRC cells, and restrained its proliferation. Besides the suppression of the MET signaling pathway, anlotinib also inhibited invasion and migration of CRC cells. Furthermore, anlotinib prevented VEGF-induced angiogenesis, N-cadherin (CDH2)-induced cell migration, and reversed ATP-binding cassette subfamily B member 1 (ABCB1) -mediated CRC multidrug resistance in CRC. The CRC liver metastasis and subcutaneously implanted xenograft model testified that anlotinib could inhibit proliferation and liver metastasis in CRC cells. Such an observation suggested that a combination of anlotinib with anti-cancer drugs could attenuate angiogenesis, metastasis, proliferative, and multidrug resistance, which constitutes a novel treatment strategy for CRC patients with metastasis.

Hybrid Magnetic Micropillar Arrays for Programmable Actuation.

Stimuli-responsive micro/nanostructures that can dynamically and reversibly adapt their configurations according to external stimuli have stimulated a wide scope of engineering applications, ranging from material surface engineering to micromanipulations. However, it remains a challenge to achieve a precise local control of the actuation to realize applications that require heterogeneous and on-demand responses. Here, a new experimental technique is developed for large arrays of hybrid magnetic micropillars and achieve precise local control of actuation using a simple magnetic field. By manipulating the spatial distribution of magnetic nanoparticles within individual elastomer micropillars, a wide range of the magnetomechanical responses from less than 5% to ≈50% for the ratio of the bending deflection to the original length of the pillars is realized. It is demonstrated that the micropillars with different degrees of bending deformation can be configured in any spatial pattern using a photomask-assisted template-casting technique to achieve heterogeneous, site-specific, and programmed bending actuations. This unprecedented local control of the micropillars offers exciting novel applications, as demonstrated here in encryptable surface printing and stamping, direction- and track-programmable microparticle/droplet transport, and smart magnetic micro-tweezers. The hybrid magnetic micropillars reported here provide a versatile prototype for heterogeneous and on-demand actuation using programmable stimuli-responsive micro/nanostructures.

Circular RNA Profiling Reveals That circRNA_104433 Regulates Cell Growth by Targeting miR-497-5p in Gastric Cancer.

BACKGROUND: The role and mechanism of hsa_circRNA_104433 in gastric cancer (GC) are further elucidated. MATERIALS AND METHODS: CircRNA_104433 was selected by circRNA microarrays and GEO database. qRT-PCR was used to analyze the expression of circRNA_104433 in GC. The role of circRNA_104433 in GC cells was evaluated based on cell cycle progression, cell proliferation, cell apoptosis, and tumor xenograft experiment assay. To explore the mechanisms of circRNA_104433 in GC TCGA database, STRING version, qRT-PCR and luciferase assay were performed. Furthermore, the prognostic value of CDC25A in GC was determined based on the GEO database. RESULTS: The level of circRNA_104433 showed upregulation in GC tissues, and the expression of it showed a positive correlation with the degree of differentiation and the size of the tumor. Knockdown of circRNA_104433 inhibited cell cycle transition, and cell proliferation, while promoted cell apoptosis in GC. CircRNA_104433 directly binds to miR-497-5p, which directly regulates CDC25A. The median survival period of GC patients with high expression levels of CDC25A was 21.3 months, which was shorter than those with low group expression of CDC25A (35.9 months). The cell cycle proteins CDK1, CDK2, CCNB1, PKMYT1, CDC20, CHEK1 and CDC25A were coexpressed with CDC25A. CONCLUSION: These findings suggested that knockdown of circRNA_104433 expression suppressed tumor development in GC.

Targeting snoRNAs as an emerging method of therapeutic development for cancer.

The relevance of the dysregulation of snoRNAs in human cancer has been widely investigated and has challenged the view that snoRNAs merely function as house-keeping genes for the posttranscriptional modification of rRNAs. Accumulating evidence has shown the intimate connection between snoRNAs and proliferation, apoptosis, invasion and migration of tumor cells via manual intervention patterns of snoRNA expression. In this review, we focused on how snoRNAs are dysregulated and its regulation of the formation and development of cancer. We summarized the non-classical functions of snoRNAs in the context of their regulations of the signaling pathways involving PI3K-AKT and K-Ras and p53-dependant manner. Under these novel functions and characteristics, snoRNAs can act as potential and feasible biomarkers for diagnosis. Simultaneously, these promising therapeutic strategies should be considered to counteract the perturbations of snoRNAs.

MiR-1284 suppresses gastric cancer progression by targeting EIF4A1.

Background: MicroRNAs (miRNAs) play a key role in the development of gastric cancer (GC). MiRNA arrays showed that lymph node metastasis in GC is correlated with the expression of miR-1284. Although its function and mechanisms in GC have not been fully described, the regulation of EIF4A1 by miR-1284 and its role in drug-resistant GC has been reported in our previous studies. Methods: qRT-PCR was used to study the level of miR-1284 expression in GC cell lines and tissues. Subsequently, the CCK-8 assay was used to detect cell proliferation, while transwell assay was used to detect invasion and migration of the GC cells. Flow cytometry was used to detect the effect of miR-1284 on GC cells in vivo by building subcutaneous GC nude mice transplantation tumor model. In addition, the influence of miR-1284 gene expression profile in SGC-7901 cells was detected by total gene expression chip, and the target gene of miR-1284 was detected by luciferase reporter assay, qRT-PCR, and western blotting. Results: The miR-1284 level was down-regulated in GC tssues and cell lines. MiR-1284 was significantly associated with tumor size, degree of differentiation and patients' distant metastasis. MiR-1284 inhibited invasion, migration, and proliferation of GC cells. During the G1/S phase, miR-1284 arrested the cycle of GC cells in vitro. MiR-1284 also suppressed tumor from growing and metastasizing in xenograft models as well as influenced the gene expression profile in SGC-7901 cells. Also, EIF4A1 was the direct target gene for miR-1284. Further, an inverse correlation between the miR-1284 expression and EIF4A1 was found in GC tissues. Over-expressed miR-1284 decreased c-Myc, MMP12, JUN expression, while increased CDH1 expression. Conclusion: These data suggested that miR-1284 acts as a tumor suppressor, and directly blocked EIF4A1 in GC.

Regulation of cell proliferation and metastasis by microRNA-593-5p in human gastric cancer.

BACKGROUND: MicroRNA (miRNA) array analysis has reported that the expression of miR-593-5p is associated with lymph node metastasis in gastric cancer (GC); however, the function and mechanism of miR-593-5p in GC have not been described yet. miR-593-5p has also not been elucidated widely in other cancers. METHODS: miR-593-5p expression was detected by quantitative RT-PCR (qRT-PCR) in human GC tissues and cell lines. Cell proliferation was investigated using CCK-8 assays, cell cycle was detected by flow cytometric method, and cell migration and invasion abilities were evaluated by wound-healing and transwell assays. miR-593-5p-influenced gene expression profiles were detected by total gene expression chip method in MGC-803 cells, and miR-593-5p candidate target genes were predicted using bioinformatics methods. The candidate target gene and downstream of miR-593-5p were determined by qRT-PCR, Western blot, and dual-luciferase reporter assays. The effects of miR-593-5p on the growth and metastasis of GC were evaluated by tumor xenograft experiment in vivo. RESULTS: miR-593-5p was frequently downregulated in GC patients and GC cell lines. miR-593-5p was significantly correlated with tumor size and distant metastasis in GC patients. miR-593-5p inhibited cell proliferation, migration, and invasion and also arrested cell cycle at the G0/G1 phase in SGC-7901 and MGC-803 cells in vitro. miR-593-5p also suppressed tumor growth and metastasis in vivo. miR-593-5p influenced gene expression profile in MGC-803 cells. MST4 was indirectly targeted by miR-593-5p. miR-593-5p also downregulated FAK, MMP12, and JUN protein expression. CONCLUSION: Our study suggests that miR-593-5p may function as a tumor suppressor in GC through a mechanism that regulates JUN pathway via indirectly targeting the MST4 gene.

Prolonging Gastrointestinal-Stromal-Tumor-free life, an optimal suggestion of imatinib intervention ahead of operation.

Background: Imatinib has been regarded as the first successful synthetic small molecule targeting at blocking tyrosine kinase. Its high efficacy stabilized disease in above 80% of chronic myeloid leukemia (CML) patients over 10 years survival. Due to the similar canceration of gastrointestinal stromal tumor (GIST) as to CML, imatinib has been approved to be used as first-line treatment. Study design: Our retrospective study was proposed to enroll 191 GIST patients with larger tumor size (≥8 cm) who preoperative accepted imatinib from those with direct operation. Analysis included demographics, cancer specific survival and relationship of their risk factors. Results: Male patients and gastrointestinal (GI) tract location took higher proportion in total cases, detection of KIT mutant took 89.7% among all traceable genetic testing. Patients with preoperative imatinib can achieve higher cancer specific survival (CSS) after both in 1 year and 3 years duration than their counterpart. Tumor size above its threshold of 8 cm would be a hazardous factor for poor prognosis. Conclusion: In conclusion, as for regressing tumor progression and creating operative chance, preoperative imatinib should be considered for the patients with high risk, although the precise duration of this intervention needs further validation.

Central Role of CEMIP in Tumorigenesis and Its Potential as Therapeutic Target.

CEMIP (KIAA1199) was identified as migratory indicator protein which had been crudely studied in the last decade. Firstly its mutation site was reported to cause hearing loss due to the folding change of protein structure, meanwhile the over-expression of CEMIP referred to dreadful invasion and uncontrolled proliferation of tumor with distant metastasis, dedifferentiation, and limited survival opportunity of patients. Especially, over-expressed CEMIP also protected malignant tumor from strict microenvironment in hypoxia, low glucose and cracked barrier, leading to enhanced adaptability of tumor by stimulating the Wnt, EGFR, FGFR pathway. Here, we intend to elaborate the clinical function and dysregulation of CEMIP under the tumorous circumstance since CEMIP plays an important role in cytokine pathway and its over-expression in tumors provide a novel target for individual therapy. Targeting CEMIP would thereby dysregulate the cytokine pathway which would in turn, decide the growth and death of the vicious tumour cells.

E2F-1 promotes DAPK2-induced anti-tumor immunity of gastric cancer cells by targeting miR-34a.

Activation of the transcription factor E2F-1 gene is a negative event in dendritic cell (DC) maturation process. Down-regulation of E2F1 causes immaturity of DC thereby stopping antigen production which in turn leads to inhibition of immune responses. E2F-1-free stimulates the NF-kB signaling pathway, leading to activation of monocytes and several other transcription factor genes. In the study, we report that down-regulation of E2F-1 in DCs promote anti-tumor immune response in gastric cancer (GC) cells through a novel mechanism. DCs were isolated from peripheral blood mononuclear cells. E2F-1 small interfering RNA (E2F-1-shRNA) induced down-regulation of E2F-1 mRNA and protein expression in DCs. Furthermore, we identified the E2F-1-shRNA targeted the CD80, CD83, CD86, and MHC II molecules, promoted their expression, and induced T lymphocytes proliferation activity and up-regulation of IFN-I³ production and GC cell killing effect, which significantly correlated with the cytotoxic T lymphocytes activated by E2F-1-shRNA DCs. The higher expression of miR-34a was found which was significantly correlated with the DC enhancing anti-tumor immunity against gastric cancer cell, and miR-34a potently targeted DAPK2 and Sp1, both of which were involved in the deactivation of E2F-1. Moreover, in E2F-1-DC-down-regulation in mice, GC transplantation tumors displayed down-regulation of Sp1, DAPK2, Caspase3, and Caspase7 and progressed to anti-tumor immunity. Collectively, our data uncover an E2F-1-mediated mechanism for the control of DC anti-tumor immunity via miR-34a-dependent down-regulation of E2F-1 expression and suggest its contribution to GC immunotherapy.

miR-135a promotes gastric cancer progression and resistance to oxaliplatin.

Resistance to oxaliplatin (OXA)-based chemotherapy regimens continues to be a major cause of gastric cancer (GC) recurrence and metastasis. We analyzed GC samples and matched non-tumorous control stomach tissues from 280 patients and found that miR-135a was overexpressed in GC samples relative to control tissues. Tumors with high miR-135a expression were more likely to have aggressive characteristics (high levels of carcino-embryonic antigen, vascular invasion, lymphatic metastasis, and poor differentiation) than those with low levels. Patients with greater tumoral expression of miR-135a had shorter overall survival times and times to disease recurrence. Furthermore, miR-135a, which promotes the proliferation and invasion of OXA-resistant GC cells, inhibited E2F transcription factor 1 (E2F1)-induced apoptosis by downregulating E2F1 and Death-associated protein kinase 2 (DAPK2) expression. Our results indicate that higher levels of miR-135a in GC are associated with shorter survival times and reduced times to disease recurrence. The mechanism whereby miR-135a promotes GC pathogenesis appears to be the suppression of E2F1 expression and Sp1/DAPK2 pathway signaling.

MTRR silencing inhibits growth and cisplatin resistance of ovarian carcinoma via inducing apoptosis and reducing autophagy.

Methionine synthase reductase (MTRR) is involved in the DNA synthesis and production of S-adenosylmethionine (SAM) and plays an important role in the carcinogenesis. However, the role of MTRR in the resistance of ovarian cancer (OC) to chemotherapy has yet to be elucidated. In order to investigate the clinical significance of MTRR in OC, MTRR expression was reduced by using the RNA interference technique, and therefore, and the tumor growth and cisplatin-resistance were evaluated in vitro and in vivo. Results showed MTRR expression increased orderly from normal tissues, benign ovarian tumor to OC tissue. MTRR over-expression in OC tissue was correlated with pathologic type (P=0.005), grade (P=0.037), FIGO stage (P=0.001), organ metastasis (P=0.009) and platinum resistance (P=0.038). MTRR silencing inhibited cell proliferation, cisplatin resistance and autophagy, and induced apoptosis of OC cells. In addition, MTRR silencing also affected the caspase expression as well as mTOR signaling pathway. Further, the tumor volume in MTRR-suppressed SKOV3/DDP mice treated with cisplatin significantly decreased when compared with controls (P<0.05). In summary, MTRR expression, which is increased in human OC, is related to the differentiation and cisplatin resistance of OC cells. MTRR silencing inhibits cell growth and cisplatin resistance by regulating caspase expression and mTOR signaling pathway in OC cells. It is suggested that MTRR may be a potential target for the therapy of OC.