Results from case-control studies and prospective studies suggest that diet is involved in the causation of large bowel cancer either as initiator, promoter or inhibitor of carcinogenesis. Available data are not sufficient to serve as a basis for firm specific dietary advice. In the present situation it is attractive to investigate available hypotheses within the frame work of intervention trials. The adenoma appears to be one of the most appropriate end point of intervention studies. Several arguments indicate that the adenoma-carcinoma sequence is a multistep process. Colorectal cancer could possibly be prevented by intervening in the development of a small adenoma or in the growth into a large adenoma. Four intervention trials have been published so far. One of them suggest a protective effect of antioxidants vitamins on adenoma recurrence and three of them conclude to the absence of effect of these vitamins. A protective effect of lactulose on adenoma recurrence has also been suggested. Three studies are currently evaluating the effect of calcium supplementation on adenoma recurrence or growth of calcium supplementation, three studies the effect of fibre supplements, two studies the effect of antioxidants (one of them with calcium) and two studies the effect of diet intervention. The results of these studies will be available within three years.

Primary prevention of colorectal cancer

Four distinct MAP kinase signaling pathways involving 7 MEK enzymes have been identified. MEK1 and MEK2 are the prototype members of MEK family proteins. Several MEK inhibitors are in clinical trials. Trametinib is being evaluated by FDA for the treatment of metastatic melanoma with BRAF V600 mutation. Selumetinib has been studied in combination with docetaxel in phase II randomized trial in previously treated patients with advanced lung cancer. Selumetinib group had better response rate and progression-free survival. This review also summarized new MEK inhibitors in clinical development, including pimasertib, refametinib, PD-0325901, TAK733, MEK162 (ARRY 438162), RO5126766, WX-554, RO4987655 (CH4987655), GDC-0973 (XL518), and AZD8330.

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MEK and the inhibitors: from bench to bedside.

Long non-coding RNAs (lncRNAs) are a group greater than 200 nucleotides in length. An increasing number of studies has shown that lncRNAs play important roles in diverse cellular processes, including proliferation, differentiation, apoptosis, invasion and chromatin remodelling. In this regard, deregulation of lncRNAs has been documented in human cancers. TUG1 is a recently identified oncogenic lncRNA whose aberrant upregulation has been detected in different types of cancer, including B-cell malignancies, oesophageal squamous cell carcinoma, bladder cancer, hepatocellular carcinoma and osteosarcoma. In these malignancies, knock-down of TUG1 has been shown to suppress cell proliferation, invasion and/or colony formation. Interestingly, TUG1 has been found to be downregulated in non-small cell lung carcinoma, indicative of its tissue-specific function in tumourigenesis. Pertinent to clinical practice, TUG1 may act as a prognostic biomarker for tumours. In this review, we summarize current knowledge concerning the role of TUG1 in tumour progression and discuss mechanisms associated with it.

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CCAT1: a pivotal oncogenic long non-coding RNA in human cancers.

Accumulating evidence demonstrates the oncogenic roles of lncRNA (long non-coding RNA) molecules in a wide variety of cancer types including glioma. Equally important, However, tumorigenic functions of lncRNA in glioma remain largely unclear. A recent study suggested lncRNA SNHG15 played a role for regulating angiogenesis in glioma but its role in the tumor microenvironment (TME) was not investigated. First, we showed that SNHG15 was upregulated in GBM cells and associated with a poor prognosis for the patients of GBM using public databases. Next, we collected temozolomide sensitive (TMZ-S) and resistant (TMZ-R) clinical samples and demonstrated that co-culturing TMZ-R cells with HMC3 (microglial) cells promoted M2-polarization of HMC3 and the secretion of pro-GBM cytokines TGF-β and IL-6. Comparative qPCR analysis of TMZ-S and TMZ-R cells showed that a significantly higher level of SNHG15, coincidental with a higher level of Sox2, β-catenin, EGFR, and CDK6 in TMZ-R cells. Subsequently, using bioinformatics tool, a potential mechanistic route for SNHG15 to promote GBM tumorigenesis was by inhibiting tumor suppressor, miR-627-5p which leads to activation of CDK6. Gene-silencing technique was employed to demonstrate that suppression of SNHG15 indeed led to the suppression of GBM tumorigenesis, accompanied by an increase miR-627-5p and decreased its two oncogenic targets, CDK6 and SOX-2. In addition, SNHG15-silenced TMZ-R cells became significantly sensitive towards TMZ treatment and less capable of promoting M2-phenotype in the HMC3 microglial cells. We then evaluated the potential anti-GBM activity of CDK6 inhibitor, palbociclib, using TMZ-R PDX mouse models. Palbociclib treatment significantly reduced tumorigenesis in TMZ-R/HMC3 bearing mice and SNHG15 and CDK6 expression was significantly reduced while miR-627-5p level was increased. Additionally, palbociclib treatment appeared to overcome TMZ resistance as well as reduced M2 markers in HMC3 cells. Together, we provided evidence supporting the usage of CDK6 inhibitor for TMZ-resistant GBM cases. Further investigation is warranted for the consideration of clinical trials.

/pdf/modulating-lncrna-snhg15-cdk6-mir-627-circuit-by-palbociclib-4m2yqvv5g3.pdf

Modulating lncRNA SNHG15/CDK6/miR-627 circuit by palbociclib, overcomes temozolomide resistance and reduces M2-polarization of glioma associated microglia in glioblastoma multiforme

In the original publication of this article,[1] the Funding section needs to be revised, and the corrected Funding section appears below.

/pdf/snhg15-is-a-bifunctional-myc-regulated-noncoding-locus-1q8n9bdt51.pdf

SNHG15 is a bifunctional MYC-regulated noncoding locus encoding a lncRNA that promotes cell proliferation, invasion and drug resistance in colorectal cancer by interacting with AIF

Circular ATP binding cassette subfamily B member 10 (circABCB10) has been identified to have oncological functions in several tumors However, the roles of circABCB10 in rectal cancer remain unknown The expression of circABCB10, microRNA (miR)-326 and C-C motif chemokine ligand 5 (CCL5), and apoptosis related-protein was detected using quantitative real-time polymerase chain reaction or western blot, respectively Cell survival or apoptosis was measured using cell counting kit-8 assay or flow cytometry The accumulations of intracellular lipid reactive oxygen species (ROS) and Fe2+ were analyzed using C11-BODIP dye or iron kit assay, respectively In vivo experiments were conducted using the murine xenograft model The interaction between miR-326 and circABCB10 or CCL5 was confirmed by dual-luciferase reporter assay and RNA immunoprecipitation assay CircABCB10 and CCL5 were upregulated but miR-326 was downregulated in rectal cancer The knockdown of circABCB10 promoted rectal cancer cell ferroptosis and apoptosis in vitro as well as inhibited tumor growth in vivo miR-326 was a target of circABCB10, and the miR-326 inhibition could partially attenuate circABCB10 deletion-induced cell ferroptosis and apoptosis miR-326 directly interacted with CCL5, and the miR-326 inhibition suppressed cell ferroptosis and apoptosis by targeting CCL5 Besides, we observed that miR-326 was negatively regulated by circABCB10, while CCL5 was positively regulated by it, and circABCB10 served as a sponge of miR-326 to regulate the CCL5 expression in rectal cancer cells CircABCB10 silence promoted rectal cancer cell ferroptosis and apoptosis by regulating the miR-326/CCL5 axis, suggesting a potential therapeutic target for rectal cancer therapy

/pdf/circabcb10-silencing-inhibits-the-cell-ferroptosis-and-3v27kx6k97.pdf

CircABCB10 silencing inhibits the cell ferroptosis and apoptosis by regulating the miR-326/CCL5 axis in rectal cancer

Long noncoding RNAs (lncRNAs) play a critical role in the initiation and progression of colorectal cancer (CRC), but little is known about the function of lncRNAs in the colorectal liver metastasis (CLM). This study was designed to identify specific lncRNAs correlating to liver metastasis of CRC, and to further assess their clinical value. Seventeen patients with primary CRC lesions, adjacent normal mucosa, and synchronous liver metastases lesions were divided into discovery set (six patients) and test set (11 patients). Transcriptome sequencing (RNAseq) was used to screen differential expression of lncRNAs in the discovery set. Based on bioinformatics data, quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was used to verify the target lncRNA in test set. The relationships between target lncRNA and clinical values were analysed in an expanded validation set of additional 91 patients. 23 upregulated and 14 downregulated lncRNAs were detected for distinguishing synchronous liver metastases, primary CRC lesions from adjacent normal mucosa in the RNAseq set. The expression levels of four lncRNAs in the 37 lncRNA signature were verified by qRT-PCR in the test set. Compared with the paired normal mucosa, high expression levels of lnc-small-nucleolar RNA host gene 15 (SNHG15) were detected not only in primary CRC lesions but also in liver metastases lesions in the test set. Furthermore, in the expanded validation set, high expression of lnc-SNHG15 was significantly associated with lymph-node metastasis and liver metastasis (p < 0.05), and patients displaying high lncRNA-SNHG15 expression exhibited a shorter median overall survival duration than those displaying low expression (30.7 vs. 35.2 months; p = 0.003). Multivariate analyses demonstrated that lncRNA-SNHG15 overexpression may serve as a poor prognostic biomarker for CRC patients (p = 0.049; Cox's regression: 2.731). Lnc-SNHG15 overexpression was significantly associated with CLM and high-expression of lnc-SNHG15 in CRC was an independent predictor of poor survival.

Aberrant expression of long noncoding RNA SNHG15 correlates with liver metastasis and poor survival in colorectal cancer.

Activation of MEK5 in many cancers is associated with carcinogenesis through aberrant cell proliferation. In this study, we determined the level of phosphorylated MEK5 (pMEK5) expression in human colorectal cancer (CRC) tissues and correlated it with clinicopathologic data. pMEK5 expression was examined by immunohistochemistry in a tissue microarray (TMA) containing 335 clinicopathologic characterized CRC cases and 80 cases of nontumor colorectal tissues. pMEK5 expression of 19 cases of primary CRC lesions and paired with normal mucosa was examined by Western blotting. The relationship between pMEK5 expression in CRC and clinicopathologic parameters, and the association of pMEK5 expression with CRC survival were analyzed respectively. pMEK5 expression was significantly higher in CRC tissues (185 out of 335, 55.2%) than in normal tissues (6 out of 80, 7.5%; P < 0.001). Western blotting demonstrated that pMEK5 expression was upregulated in 12 of 19 CRC tissues (62.1%) compared to the corresponding adjacent nontumor colorectal tissues. Overexpression of pMEK5 in CRC tissues was significantly correlated to the depth of invasion (P = 0.001), lymph node metastasis (P < 0.001), distant metastasis (P < 0.001) and high preoperative CEA level (P < 0.001). Consistently, the pMEK5 level in CRC tissues was increased following stage progression of the disease (P < 0.001). Analysis of the survival curves showed a significantly worse 5-year disease-free (P = 0.002) and 5-year overall survival rate (P < 0.001) for patients whose tumors overexpressed pMEK5. However, in multivariate analysis, pMEK5 was not an independent prognostic factor for CRC (DFS: P = 0.139; OS: P = 0.071). pMEK5 expression is correlated with the staging of CRC and its expression might be helpful to the TNM staging system of CRC.

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Expression of the phosphorylated MEK5 protein is associated with TNM staging of colorectal cancer

Purpose The chemoresistance of 5-fluorouracil (5-FU) limited the application of chemotherapy in colorectal cancer (CRC) treatment. Herein, we aimed to uncover the potential mechanism behind the 5-FU resistance of CRC cells. Methods The abundance of long noncoding RNA urothelial carcinoma associated 1 (lncRNA UCA1), microRNA-23b-3p (miR-23b-3p) and zinc finger protein 281 (ZNF281) was measured by quantitative real-time polymerase chain reaction (qRT-PCR) in CRC tissues and cells. Western blot was conducted to examine autophagy-related proteins, apoptosis-associated proteins and ZNF281 in CRC tissues and cells. Cell counting kit-8 (CCK8) assay was performed to detect the viability and inhibitory concentration 50% (IC50) value of 5-FU of CRC cells. The apoptosis of CRC cells was measured by flow cytometry. The binding sites between miR-23b-3p and UCA1 or ZNF281 were predicted by miRcode and Starbase software, respectively, and the combination was confirmed by dual-luciferase reporter assay and RIP assay. Murine xenograft model was established to verify the role of UCA1 on the 5-FU resistance of CRC in vivo. Results The 5-FU resistance of CRC was positively related to the level of UCA1 and autophagy. UCA1 accelerated the 5-FU resistance of CRC cells through facilitating autophagy and suppressing apoptosis. MiR-23b-3p was a target of UCA1 in 293T and CRC cells. The knockdown of miR-23b-3p reversed the inhibitory effects of UCA1 interference on the 5-FU resistance and autophagy and the promoting impact on the apoptosis of CRC cells. ZNF281 could bind to miR-23b-3p in 293T cells. MiR-23b-3p elevated the 5-FU sensitivity through down-regulating ZNF281 in CRC cells. UCA1 interference enhanced the 5-FU sensitivity of CRC through miR-23b-3p/ZNF281 axis in vivo. Conclusion UCA1 mediated 5-FU resistance of CRC cells through facilitating autophagy and inhibiting apoptosis via miR-23b-3p/ZNF281 axis in vivo and in vitro.

lncRNA UCA1 Contributes to 5-Fluorouracil Resistance of Colorectal Cancer Cells Through miR-23b-3p/ZNF281 Axis.

Background: It was reported that circular RNAs (circRNAs) exerted important functions in various human cancers. However, the function of circFAT1 was less known. The purpose of this study was to reveal the functional mechanism of circFAT1 in colorectal cancer (CRC). Materials and Methods: Quantitative real-time polymerase chain reaction and Western blot assay were used to detect the levels of genes. Cell proliferation ability was assessed by 3-(4, 5-dimethyl-2-thiazoyl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Flow cytometry was used to investigate cell apoptosis rate. The glucose consumption and lactate production were determined using related kits. Furthermore, the interaction between circFAT1 or ubiquitin-like PHD and RING finger domain-containing protein 1 (UHRF1) and miR-520b or miR-302c-3p was predicted by starbase3.0, and then confirmed by the dual-luciferase reporter assay. Besides, xenograft experiment was performed to analyze the effect of circFAT1 on tumor growth in vivo. Results: The levels of circFAT1 and UHRF1 were increased, as well as the levels of miR-520b and miR-302c-3p were decreased in CRC tissues and cells. CircFAT1 knockdown suppressed cell proliferation, cycle, and glycolysis as well as induced apoptosis. Interestingly, circFAT1 was a sponge of miR-520b and miR-302c-3p, and miR-520b and miR-302c-3p could target UHRF1. Both miR-520b overexpression and miR-302c-3p overexpression inhibited CRC cell growth. Furthermore, both miR-520b knockdown and miR-302c-3p depletion weakened the effect of circFAT1 knockdown on the growth of CRC cells. Besides, circFAT1 depletion repressed tumor growth in vivo. Conclusion: The authors' findings suggested that circFAT1 upregulated UHRF1 to affect CRC cell proliferation, apoptosis, and glycolysis through targeting miR-520b and miR-302c-3p, providing theoretical basis for the treatment of CRC.

Zhenyu Xian

Papers

CircABCB10 silencing inhibits the cell ferroptosis and apoptosis by regulating the miR-326/CCL5 axis in rectal cancer

Aberrant expression of long noncoding RNA SNHG15 correlates with liver metastasis and poor survival in colorectal cancer.

Expression of the phosphorylated MEK5 protein is associated with TNM staging of colorectal cancer

lncRNA UCA1 Contributes to 5-Fluorouracil Resistance of Colorectal Cancer Cells Through miR-23b-3p/ZNF281 Axis.

CircFAT1 Suppresses Colorectal Cancer Development Through Regulating miR-520b/UHRF1 Axis or miR-302c-3p/UHRF1 Axis.