Inhibition of triple­negative breast cancer proliferation and motility by reactivating p53 and inhibiting overactivated Akt.

Mutations of p53 tumor suppressors occur more frequently in cancers at advanced stages or in more malignant cancer subtypes such as triple­negative breast cancer. Thus, restoration of p53 tumor suppressor function constitutes a valuable cancer therapeutic strategy. In the present study, it was revealed that a specific inhibitor of histone deacetylase 6, ACY­1215, caused increased acetylation of p53 in breast cancer cells with mutated p53, which was accompanied by increased expression of p21. These results suggested that ACY­1215 may lead to enhanced transcriptional activity of p53. It was also determined that ACY­1215 treatment resulted in G1 cell cycle arrest and apoptosis in these cancer cells. Furthermore, ACY­1215 displayed a synergistic effect with specific inhibitors of ATM, an activator of Akt, in inducing cancer cell apoptosis and inhibiting their motility. More importantly, it was observed that combination of ACY­1215 and ATM inhibitors exhibited markedly more potent antitumor activity than the individual compound in xenograft mouse models of breast cancer with mutant p53. Collectively, our results demonstrated that ACY­1215 is a novel chemotherapeutic agent that could restore mutant p53 function in cancer cells with strong antitumor activity, either alone or in combination with inhibitors of the ATM protein kinase.

Inhibition of indoleamine 2,3-dioxygenase 1 synergizes with oxaliplatin for efficient colorectal cancer therapy.

We investigated the immunogenic cell death provoked by oxaliplatin (OXA) and the involvement of OXA-induced immunosuppression in colorectal cancer. Immune-proficient or -deficient mice were employed to evaluate the therapeutic effects of OXA. Immunogenic cell death was characterized by cell-surface calreticulin, cytosol-translocated high migration rate group protein B1 (HMGB1), and secretory ATP content. Bone marrow-derived dendritic cell (BMDC) maturation and CD8+ T cell expansion were measured by flow cytometry. Expression of immunosuppressive genes was quantified by both RT-PCR and western blots. The proliferative and apoptotic indexes of xenograft tumors were evaluated by immunohistochemistry and TUNEL assays, respectively. The secretory cytokines were measured with ELISA. OXA induced immunogenic cell death of murine colorectal cancer, which greatly depended on the host immune response. OXA-pretreated CT26 cells promoted BMDC maturation and CD8+ T cell expansion. OXA significantly upregulated indoleamine 2,3-dioxygenase 1 (IDO1) in patient-derived colorectal cancer cells and in combination with the IDO1-specific inhibitor, NLG919, suppressed tumor progression. Simultaneous administration with both OXA and NLG919 greatly promoted CD8+ T cell infiltration and decreased immunosuppressive cytokine transforming growth factor ß (TGF-ß) production, whereas increased immunostimulatory cytokines interleukin (IL)-12p70 and interferon (IFN)-γ. We demonstrated the upregulation of IDO1 by OXA, which combined with the IDO1 inhibitor, tremendously potentiated therapeutic effects of OXA against colorectal cancer.

ATM inhibitor KU-55933 induces apoptosis and inhibits motility by blocking GLUT1-mediated glucose uptake in aggressive cancer cells with sustained activation of Akt.

Enhanced glucose uptake is coupled with elevated aerobic glycolysis (the Warburg effect) in cancer cells and is closely correlated with increased tumor aggressiveness and poor prognosis. We previously discovered that ATM, a protein kinase deficient in Ataxia-telangiectasia (A-T) disease, is an insulin-responsive protein that participates in insulin-mediated glucose uptake in muscle cells by stimulating glucose transporter 4 (GLUT4) translocation. However, the role of ATM in glucose uptake and tumorigenesis of cancer cells is unclear. In the present study, we found that aggressive breast and prostate cancer cell lines with overactivated Akt activity exhibit enhanced glucose uptake and GLUT1 translocation upon insulin treatment, and KU-55933, a specific inhibitor of ATM, inhibits insulin-mediated glucose uptake by blocking translocation of GLUT1 to the cell surface. KU-55933 also inhibits aerobic glycolysis and ATP production in these cells. Moreover, KU-55933 induces apoptosis and inhibits motility of cancer cells by inhibiting glucose uptake. Our results showed that while high concentration of glucose and insulin promote the expression of a mesenchymal biomarker (vimentin) in these cancer cells, KU-55933 strongly inhibits its expression as well as epithelial to mesenchymal transition. The roles of ATM in stimulating glucose uptake, glycolysis, motility, and proliferation of cancer cells were demonstrated by knocking-down ATM in these cells. KU-55933 treatment also inhibits tumor growth and metastasis in vivo in mouse mammary tumors through inhibition of GLUT1 translocation and vimentin expression. These results suggest that ATM acts as a promoter of tumorigenesis in cancer cells with overactivated Akt, and KU-55933 induces apoptosis and inhibits motility by blocking GLUT1-mediated glucose uptake and glycolysis in these cancer cells, which may lead to the use of KU-55933 and its analogs as new preventive or therapeutic agents against cancer.

Circ-SMARCA5 suppresses colorectal cancer progression via downregulating miR-39-3p and upregulating ARID4B.

BACKGROUND: Circular RNAs are crucial in tumorigenesis. However, little is known about their functions in colorectal cancer (CRC). Circ-SMARCA5 was found to be an oncogene or tumor suppresser in different types of cancers, but its exact role in CRC remains unknown. Here, we aim to identify the role of circ-SMARCA5 in CRC development. METHODS: Circ-SMARCA5 expression was determined by qRT-PCR. CRC cell proliferation, migration, and invasion were detected by CCK-8, wound healing, and Transwell assays, respectively. Bioinformatics analysis was performed to predict target genes. The interaction of microRNA (miR) with circ-SMARCA5 or target genes was detected using luciferase reporter assay. Xenograft model was established to determine the effect of circ-SMARCA5 on CRC tumor growth in vivo. RESULTS: Circ-SMARCA5 expression was dramatically decreased in CRC cell lines and tissues. Circ-SMARCA5 overexpression inhibited CRC cell proliferation, migration and invasion. MiR-93-3p was predicted as a target of circ-SMARCA5 and its overexpression attenuated the anti-tumor effect of circ-SMARCA5 on CRC cells. Furthermore, we predicted AT-rich interaction domain 4B (ARID4B) as the target of miR-39-3p. Functional analysis showed that circ-SMARCA5 upregulated ARID4B expression via miR-39-3p. Additionally, in vivo studies demonstrated that circ-SMARCA5 suppressed CRC tumor progression. CONCLUSION: Circ-SMARCA5 functions as a tumor suppressor by upregulating ARID4B expression via sponging miR-39-3p, and thereby inhibited CRC progression.

Ferritin Light Chain (FTL) competes with long noncoding RNA Linc00467 for miR-133b binding site to regulate chemoresistance and metastasis of colorectal cancer.

Although the colorectal cancer (CRC) mortality rates are decreasing in virtue of CRC screening and improved therapeutic methods, CRC is still a leading cause of cancer deaths. One of the main causes is chemoresistance occurrence in CRC. Understanding of the molecular mechanisms of chemoresistance benefits to CRC diagnosis and treatment. In this study, gene expression was determined by western blot and qRT-PCR. The biological functions of genes in CRC cells were studied by knocking down or overexpressing the gene in CRC cells and then analyzing cell sensitivity to 5-Fu by the MTT assay and the flow cytometry, and analyzing cell migration and invasion by transwell assays. The luciferase reporter assay was used to examine microRNA regulation of target gene expression, and biotin pull-down assay was performed to detect interaction between RNA molecules. This study found that ferritin light chain (FTL) and long intergenic noncoding RNA Linc00467 were both upregulated in CRC tissues and cell lines, and inversely correlated to CRC patient survival. FTL and Linc00467 promoted CRC cells abilities to resistance against 5-fluor-ouracil (5-Fu), migration and invasion. These effects were compromised by miR-133b which targeted both FTL and Linc00467. miR-133b interacted with Linc00467 and miR-133b inhibitor prevented Linc00467 knockdown-induced alternations of FTL expression and biological functions. Both FTL and Linc00467 are oncogenes in CRC. FTL expression upregulated in CRC via Linc00467/ miR-133b axis, and leads to CRC cell resistance against 5-FU treatment and promotes CRC metastasis. FTL expression upregulated in CRC via Linc00467/miR-133b axis, and leads to CRC cell resistance to 5-FU treatment and promotes CRC metastasis.

MiR-4319 suppresses colorectal cancer progression by targeting ABTB1.

Background: Colorectal cancer is one of the highly malignant cancers with a poor prognosis. The exact mechanism of colorectal cancer progression is not completely known. Recently, microRNAs (miRNAs, miRs) were suggested to participate in the regulation of multiple cancer development, including colorectal cancer. Methods: MiR-4319 expression in colorectal cancer patient samples was detected by real-time polymerase chain reaction. MiR-4319 was knocked down in the colorectal cancer cells by siRNA transfection to study the role of miR-4319 in the cell cycle and proliferation of colorectal cancer cells. Results: MiR-4319 expression was found to be inverse correlated with survival in colorectal cancer patients. Overexpression of miR-4319 markedly reduced the proliferation of colorectal cancer cells and altered cell cycle distribution. A further experiment showed that ABTB1 is the target gene of miR-4319. MiR-4319 was regulated by PLZF. Conclusion: Our studies indicated that reduced expression of miR-4319 was correlated with poor prognosis in colorectal cancer patients; miR-4319 also suppressed colorectal cancer cell proliferation by targeting ABTB1. ABTB1 might become an excellent therapeutic target for colorectal cancer treatment.

A new biosensor detection system to overcome the Debye screening effect: dialysis-silicon nanowire field effect transistor.

Background: A silicon nanowire field effect transistor biosensor has four advantages in the detection of small biomolecules. It is mark-free, immediately responsive, highly sensitive, and specific. However, because of environments with a high salt concentration, the Debye screening effect has been a major issue in biological detection. Objective: To overcome Debye screening effect, realize the clinical application of silicon nanowire field effect transistor and verify its specificity and sensitivity. Materials and methods: The test solution was desalted by miniature blood dialyzer, and then the tumor markers were detected by silicon nanowire field effect transistor. Results: Tumor markers in serum were detected successfully and their sensitivity and specificity were verified. Conclusion: This method was found to effectively promote the development of semiconductor materials in biological solution detection.

Indocyanine Green Fluorescence Angiography and the Incidence of Anastomotic Leak After Colorectal Resection for Colorectal Cancer: A Meta-analysis.

BACKGROUND: Anastomotic leak is a life-threatening complication of colorectal surgery. Recent studies showed that indocyanine green fluorescence angiography might be a method to prevent anastomotic leak. OBJECTIVE: The purpose of this study was to investigate whether intraoperative indocyanine green fluorescence angiography can reduce the incidence of anastomotic leak. DATA SOURCES: Potential relevant studies were identified from the following databases: PubMed, Embase, Web of Science, Cochrane Library, and China National Knowledge Infrastructure. STUDY SELECTION: This meta-analysis included comparative studies investigating the association between indocyanine green fluorescence angiography and anastomotic leak in patients undergoing surgery for colorectal cancer where the diagnosis of anastomotic leak was confirmed by CT and the outcomes of the indocyanine green group were compared with a control group. INTERVENTION: Indocyanine green was injected intravenously after the division of the mesentery and colon but before anastomosis. MAIN OUTCOME MEASURES: The Newcastle-Ottawa Scale was used to assess methodologic quality of the studies. ORs and 95% CIs were used to assess the association between indocyanine green and anastomotic leak. RESULTS: In 4 studies with a total sample size of 1177, comparing the number of anastomotic leaks in the indocyanine green and control groups, the ORs were 0.45 (95% CI, 0.18-1.12), 0.30 (95% CI, 0.03-2.98), 0.17 (95% CI, 0.01-3.69), and 0.12 (95% CI, 0.03-0.52). The combined OR was 0.27 (95% CI, 0.13-0.53). The difference was statistically significant (p < 0.001), and there was no significant heterogeneity (p = 0.48; I = 0). LIMITATIONS: Data could not be pooled because of the small number of studies; some differences between studies may influence the results. Also, the pooled data were not randomized. CONCLUSIONS: The result revealed that indocyanine green was associated with a lower anastomotic leakage rate after colorectal resection. However, larger, multicentered, high-quality randomized controlled trials are needed to confirm the benefit of indocyanine green fluorescence angiography.

Ursolic acid enhances the therapeutic effects of oxaliplatin in colorectal cancer by inhibition of drug resistance.

It has been reported that ursolic acid has anti-tumor activity and it enhances the therapeutic effect of oxaliplatin in colorectal cancer (CRC). However, the underlying mechanisms remain unknown. In the present study, the mechanisms of the enhancement of therapeutic effects through use of ursolic acid were investigated. We treated CRC cell lines HCT8 and SW480 with ursolic acid and oxaliplatin and monitored the effects on cell proliferation, apoptosis, reactive oxygen species (ROS) production and drug resistance gene production. We discovered that treatment with a combination of ursolic acid and oxaliplatin resulted in significant inhibition of cell proliferation, significantly increased apoptosis and ROS production, and significant inhibition of drug resistance gene expression. Our study provided evidence that ursolic acid enhances the therapeutic effects of oxaliplatin in colorectal cancer by ROS-mediated inhibition of drug resistance.

Curcumin Suppresses the Colon Cancer Proliferation by Inhibiting Wnt/ß-Catenin Pathways via miR-130a.

Curcumin exhibits anti-tumor effects in several cancers, including colorectal carcinoma (CRC), but the detailed mechanisms are still unclear. Here we studied the mechanisms underlying the anti-tumor effect of curcumin in colon cancer cells. SW480 cells were injected into mice to establish the xenograft tumor model, followed by evaluation of survival rate with the treatment of curcumin. The expression levels of ß-catenin, Axin and TCF4 were measured in the SW480 cells in the absence or presence of curcumin. Moreover, miRNAs related to the curcumin treatment were also detected in vitro. Curcumin could suppress the growth of colon cancer cells in the mouse model. This anti-tumor activity of curcumin was exerted by inhibiting cell proliferation rather than promoting cell apoptosis. Further study suggested that curcumin inhibited cell proliferation by suppressing the Wnt/ß-catenin pathway. MiR-130a was down-regulated by curcumin treatment, and overexpressing miR-130a could abolish the anti-tumor activity of curcumin. Our study confirms that curcumin is able to inhibit colon cancer by suppressing the Wnt/ß-catenin pathways via miR-130a. MiR-130a may serve as a new target of curcumin for CRC treatment.