Blocking the IGF2BP1-promoted glucose metabolism of colon cancer cells via direct de-stabilizing mRNA of the LDHA enhances anticancer effects.

Colorectal cancer (CRC) is a commonly diagnosed cancer with poor prognosis and high mortality rate. Hyperthermia (HT) is an adjunctive therapy to enhance the antitumor effects of traditional chemo- or radio- therapy. Here, we report that a cluster of essential regulator genes and speed-limit enzymes of glucose metabolism were significantly elevated under HT from a glucose metabolism PCR array analysis. Under low glucose supply or glucose metabolism inhibition, CRC cells displayed increased sensitivity to HT treatments. By transcript sequencing from the established HT resistant (HTR) colon cancer cell line LoVo HTR, we observed that IGF2BP1, an RNA-binding protein, was significantly upregulated in HTR cells compared with parental cells. Furthermore, LDHA mRNA was identified as an IGF2BP1 direct target. An RNA immunoprecipitation assay and RNA pull-down assay consistently illustrated IGF2BP1 specifically bonds to the 3' UTR of LDHA mRNA, leading to enhanced stability of LDHA mRNA. Finally, we demonstrated that inhibiting the IGF2BP1-promoted glycolysis sensitized colon cancer cells to HT treatment via both in vitro and in vivo experiments. Our findings suggest that targeting the IGF2BP1-LDHA-glycolysis pathway might be a promising therapeutic approach to enhance the anti-cancer effects of HT treatment.

Elevated FOXO6 expression correlates with progression and prognosis in gastric cancer.

The FOXO6 correlated with tumor progression in a wide range of carcinomas, yet little is known in gastric cancer. The expression of FOXO6 and matrix metallopeptidase 9 (MMP-9) was assessed by immunohistochemistry in 192 gastric carcinoma specimens. The correlation between FOXO6 expression with MMP-9, clinicopathological/prognostic value in gastric cancer was examined. FOXO6 overexpression was significantly associated with depth of invasion, lymph node metastasis and stage of disease. In univariate and multivariate analyses, FOXO6 was an independent prognostic factor for both overall survival (OS) and recurrence-free survival (RFS). Moreover, FOXO6 over-expression was correlated with poor prognosis in patients subgroups stratified by tumor size, depth of invasion and lymph node metastasis. FOXO6 expression was increased in both prominent serosal invasion group and lymph node metastasis group. In addition, FOXO6 expression was positively correlated with MMP-9 among 192 gastric cancer tissues. Patients with FOXO6 over-expression had poor OS and shorter RFS in low and high invasiveness groups. Furthermore, stratified analysis showed that the TNM stage I patients with high FOXO6 expression had poor prognosis than those with low FOXO6 expression. In conclusion, FOXO6 overexpression promotes tumor aggressiveness and prognosis, and could be a promising target for prognostic prediction in gastric cancer patients. CONDENSED ABSTRACT: The aim of this study was to analyze the role of FOXO6 in patients with gastric carcinoma. FOXO6 may play an important role on tumor invasion, metastasis and prognosis. It may also serve as a novel target for prognostic prediction.

Metformin depresses overactivated Notch1/Hes1 signaling in colorectal cancer patients with type 2 diabetes mellitus.

The function of metformin in colorectal cancer (CRC) patients with diabetes mellitus (DM) remains a controversial topic because studies are increasingly focusing on epidemiologic features. We examined Notch1/Hes1 signaling in CRC with DM (DM-CRC) and investigated alterations in signaling caused by metformin treatment. For this purpose, information on pathological characteristics was collected from each patient. The proliferation of epithelium labeled with proliferating cell nuclear antigen and the differentiation of goblet cells were investigated using immunohistochemistry and periodic acid-Schiff staining, respectively. The factors involved in Notch1/Hes1 signaling were detected using qRT-PCR and western blot. In our study, we found that lymphatic metastasis, pTNM staging, and the carcinoembryonic antigen level were significantly different between groups. The depth of crypts and the rate of proliferating cell nuclear antigen-positive cells were distinctly higher in DM-CRC and patients who were managed with insulin. Moreover, the goblet cell differentiation rate was decreased in DM-CRC. The expression of Dll1, Notch1, Math1, and RBP-Jκ was increased in DM-CRC, whereas the expression of Dll4 and Hes1 was decreased in this group in normal tissue. In CRC tissue, the expression of Dll1 and Notch1 was clearly higher than that in DM-CRC. Furthermore, the trend in these changes was aggravated with insulin management and alleviated with metformin treatment. In conclusion, the abnormal cell proliferation and differentiation observed in DM-CRC are correlated with overactivated Notch1/Hes1 signaling, which is potentially relieved by metformin treatment.

[Biomechanical study on the composite of allogenic decalcified bone matrix gelatin and bone cement].

OBJECTIVE: To evaluate the biomechanical properties and structural characteristics of various composites of partially decalcified allogenic bone matrix gelatin and bone cement at different ratios. METHODS: According to Urist method, partially decalcified allogenic bone matrix gelatin was prepared and mixed with bone cement at different ratios of 0, 400, 500, and 600 mg/g. Then the comparisons of these composites were performed in microstructure, ultimate compression strength and ultimate bending strength properties. RESULTS: The electronic microscope showed that the bone particles and bone cement were distributed evenly in the composite, irregularly connecting by multiple points; with the increase of bone particles and decrease of bone cement in the composite, there were more and more natural crevices, varying from 100 microns to 400 microns in width, in the biomaterials. Of all the composites with the ratios of 0, 400, 500, and 600 mg/g, the measurements of ultimate compression strength were (71.7 +/- 2.0) MPa, (46.9 +/- 3.3) MPa, (39.8 +/- 4.1) MPa, and (32.2 +/- 3.4) MPa, respectively; and the measurements of ultimate bending strength were (65.0 +/- 3.4) MPa, (38.2 +/- 4.0) MPa, (33.1 +/- 4.3) MPa and (25.3 +/- 4.6) MPa, respectively. CONCLUSION: The composite of partially decalcified allogenic bone matrix gelatin and bone cement has a good biomechanical property and could be easily fabricated and re-shaped, which make it available to be used clinically as an idea bone graft biomaterial.