Although surgery remains the mainstay of curative treatment for colorectal cancer (CRC), many patients still have high chance to experience disease relapse. It is therefore imperative to identify prognostic markers that can help predict the clinical outcomes of CRC. Aberrant microRNA expression holds great potential as diagnostic and prognostic biomarker for CRC. Here we aimed to investigate clinical potential of miR-34a-5p as a prognostic marker for CRC recurrence and its functional significance. First, we validated that miR-34a-5p was downregulated in CRC tumour tissues (P<0.05). The expression level of tissue miR-34a-5p was then evaluated in two independent cohorts of 268 CRC patients. miR-34a-5p expression was positively correlated with disease-free survival in two independent cohorts (cohort I: n=205, P<0.001; cohort II: n=63, P=0.006). Moreover, the expression of miR-34a-5p was an independent prognostic factor for CRC recurrence by multivariate analysis (P<0.001 for cohort I, P=0.007 for cohort II). Ectopic expression of miR-34a-5p in p53 wild-type colon cancer cell HCT116 significantly inhibited cell growth, migration, invasion and metastasis. miR-34a-5p induced cell apoptosis, cell cycle arrest at G1 phase and p53 transcription activity in HCT116 cells, but not in the HCT116 p53 knockout (p53(-/-)) cells. miR-34a-5p significantly suppressed the HCT116 growth in vivo, whereas it showed no effect on the HCT116 p53(-/-) xenograft, indicating that the growth-inhibiting effect by miR-34a-5p was dependent on p53. In addition, the expression level of miR-34a-5p in patients with p53-positive expression was higher than that in patients with p53-negative expression (P<0.01). In conclusion, miR-34a-5p inhibits recurrence of CRC through inhibiting cell growth, migration and invasion, inducing cell apoptosis and cell cycle arrest in a p53-dependent manner.

AimsTo test the hypothesis that delivery of integrated care augmented by a web‐based disease management programme and nurse coordinator would improve treatment target attainment and health‐related behaviour.MethodsThe web‐based Joint Asia Diabetes Evaluation (JADE) and Diabetes Monitoring Database (DIAMOND) portals contain identical built‐in protocols to integrate structured assessment, risk stratification, personalized reporting and decision support. The JADE portal contains an additional module to facilitate structured follow‐up visits. Between January 2009 and September 2010, 3586 Chinese patients with Type 2 diabetes from six sites in China were randomized to DIAMOND (n = 1728) or JADE, plus nurse‐coordinated follow‐up visits (n = 1858) with comprehensive assessments at baseline and 12 months. The primary outcome was proportion of patients achieving ≥ 2 treatment targets (HbA1c < 53 mmol/mol (7%), blood pressure < 130/80 mmHg and LDL cholesterol < 2.6 mmol/l).ResultsOf 3586 participants enrolled (mean age 57 years, 54% men, median disease duration 5 years), 2559 returned for repeat assessment after a median (interquartile range) follow‐up of 12.5 (4.6) months. The proportion of participants attaining ≥ 2 treatment targets increased in both groups (JADE 40.6 to 50.0%; DIAMOND 38.2 to 50.8%) and there were similar absolute reductions in HbA1c [DIAMOND −8 mmol/mol vs JADE −7 mmol/mol (−0.69 vs −0.62%)] and LDL cholesterol (DIAMOND −0.32 mmol/l vs JADE −0.28 mmol/l), with no between‐group difference. The JADE group was more likely to self‐monitor blood glucose (50.5 vs 44.2%; P = 0.005) and had fewer defaulters (25.6 vs 32.0%; P < 0.001).ConclusionsIntegrated care augmented by information technology improved cardiometabolic control, with additional nurse contacts reducing the default rate and enhancing self‐care. (Clinical trials registry no.: NCT01274364)

Epidemiological studies showed that obesity and its related non-alcoholic fatty liver disease (NAFLD) promote hepatocellular carcinoma (HCC) development. We aimed to uncover the genetic alterations of NAFLD-HCC using whole-exome sequencing. We compared HCC development in genetically obese mice and dietary obese mice with wild-type lean mice fed a normal chow after treatment with diethylnitrosamine. HCC tumor and adjacent normal samples from obese and lean mice were then subjected to whole-exome sequencing. Functional and mechanistic importance of the identified mutations in Carboxyl ester lipase (Cel) gene and Harvey rat sarcoma virus oncogene 1 (Hras) was further elucidated. We demonstrated significantly higher incidences of HCC in both genetic and dietary obese mice with NAFLD development as compared with lean mice without NAFLD. The mutational signatures of NAFLD-HCC and lean HCC were distinct, with <3% overlapped. Eight metabolic or oncogenic pathways were found to be significantly enriched by mutated genes in NAFLD-HCC, but only two of these pathways were dysregulated by mutations in lean HCC. In particular, Cel was mutated significantly more frequently in NAFLD-HCC than in lean HCC. The multiple-site mutations in Cel are loss-of-function mutations, with effects similar to Cel knock-down. Mutant Cel caused accumulation of cholesteryl ester in liver cells, which led to induction of endoplasmic reticulum stress and consequently activated the IRE1α/c-Jun N-terminal kinase (JNK)/c-Jun/activating protein-1 (AP-1) signaling cascade to promote liver cell growth. In addition, single-site mutations in Hras at codon 61 were found in NAFLD-HCC but none in lean HCC. The gain-of-function mutations in Hras (Q61R and Q61K) significantly promoted liver cell growth through activating the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/3-phosphoinositide-dependent protein kinase-1 (PDK1)/Akt pathways. In conclusion, we have identified mutation signature and pathways in NAFLD-associated HCC. Mutations in Cel and Hras have important roles in NAFLD-associated hepatocellular carcinogenesis.

The Ras association domain family (RASSF) encodes several members with tumor-suppressive potentials. We aimed to investigate the biological function and clinical implication of RASSF10 in gastric cancer (GC). We found that RASSF10 was silenced in six of seven GC cell lines and in primary GC tissues, but was highly expressed in normal gastric tissues. The silence of RASSAF10 was mediated by promoter methylation as evaluated by bisulfite genomic sequencing. RASSF10 expression could be restored by demethylation treatment. A negative correlation between methylation and mRNA expression of RASSF10 was observed in 223 gastric samples of The Cancer Genome Atlas study (P<0.0001). Re-expression of RASSF10 in GC cell lines (AGS and MKN45) significantly suppressed cell viability, colony formation, migration and invasion, reduced cells in S phase, accumulated cells in G2 phase and induced cell apoptosis in vitro, and inhibited tumorigenicity in nude mice. These were confirmed by decreased expression of proliferation markers (proliferating cell nuclear antigen, p-CDC2 and p-CDC25) and increased apoptotic cascades (cleaved caspases-9, -8, -3 and cleaved poly (ADP-ribose) polymerase). Conversely, RASSF10 knockdown in normal gastric cell line yielded an opposing effect. Co-immunoprecipitation combined with mass spectrometry analyses were performed to reveal the downstream effectors of RASSF10. The result revealed that glutathione S-transferase Pi 1 (GSTP1) was a direct cooperator of RASSF10. The tumor-suppressive effect of RASSF10 was partially mediated by cooperating with GSTP1 to deregulate Jun N-terminal kinase (JNK)/c-Jun/AP-1 pathway. Importantly, RASSF10 methylation was detected in 56.6% (98/173) of primary GCs and is an independent risk factor for poor survival of GC patients (P=0.001). In conclusions, RASSF10 functions as a tumor suppressor by cooperating with GSTP1 to deregulate JNK/c-Jun/AP-1 pathway in GC. Promoter methylation of RASSF10 is associated with poor survival of GC patients.

Ras-Association Domain Family 10 (RASSF10) is the last identified member of the RASSF family. The functional characteristics of this new gene in human cancers remain largely unclear. Here, we examined RASSF10 for the biological functions and related molecular mechanisms in hepatocellular carcinoma (HCC). We found that RASSF10 is expressed in normal human liver tissue, but is silenced or down-regulated in 62.5% (5/8) of HCC cell lines. The mean expression level of RASSF10 was significantly lower in primary HCCs compared with their adjacent normal tissues (P<0.005, n=52). The promoter methylation contributes to the inactivation of RASSF10 as demonstrated by bisulfite genomic sequencing and demethylation treatment analyses. Transgenic expression of RASSF10 in silenced HCC cell lines suppressed cell viability, colony formation and inhibited tumor growth in nude mice (QGY7703, P<0.01; HepG2, P<0.05). Furthermore, RASSF10 was shown to induce the cell accumulation in G1 phase with the increase of p27, as well as the decrease of cyclinD1 and CDK2/CDK4. Over-expression of RASSF10 also inhibited HCC cells migration (P<0.01) or invasion (P<0.05). Adhesion genes array revealed that Matrix Metalloproteinase 2 (MMP2) was a downstream effector of RASSF10. RASSF10 acting as a tumor suppressor to inhibit HCC invasion partially mediated by Focal Adhesion Kinase or p38 MAPK to decrease the accumulation of MMP2. Our study suggests that RASSF10 acts as a tumor suppressor for HCC.

Breast cancer is the most common disease in women around the world and the current treatment strategies are not potent enough for the patients, especially those who are the triple-negative type of molecular classifications. Therefore, novel and more effective treatments are pressingly needed. Of the current methods, target therapy, which not only retains cancer-specific expression but also limits toxicity, is a new strategy for treatment of cancers. In this study, it was to investigate miR-34a expression in breast caner specimen and its relationship with patient's clinical status, and develop targeted miR-34a delivery system as a potential method for breast cancer therapy. miR-34a expression was investigated by qRT-PCR and related to clinicopathologic significance and found to be down-regulated in breast cancer as compared with normal adjacent tissues and involved in breast cancer stem cell through down-regulation of CD44, ZEB1, and Bmi1. We designed targeted miR-34a expression using T-VISA system (hTERT promoter driven VP16-Gal4-WPRE Integrated Systemic Amplifier) liposomed-based nanoparticles and evaluated the antitumor effect in breast cancer cells in vitro and in orthotopic animal model as well as its systemic toxicity. The T-VISA-miR-34a system robust targeted to breast cancer cells and breast cancer stem cells and prolonged duration expression of miR-34a. Furthermore, a systemic delivery of a VISA –miR-34a nanoparticle system targeted efficiently expression of miR-34a to tumors and could significantly inhibit tumor growth and prolong mouse survival in multiple living imaging xenograft and syngeneic models of orthotopic breast cancer and without toxicity in intact mice. Our study demonstrated that miR-34a expression was down-regulated in breast cancer and breast cancer stem cells through down-regulation of CD44, ZEB1, and Bmi1. The T-VISA-miR-34a nanoparticle system showed robust antitumor effects in breast cancer and could be a potential therapeutic approach to eradicating breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-10-10.

Background: To date, there is no suitable serum marker for diagnosis and prognosis of breast cancer. In our early research, a new tumor marker candidate of breast cancer whose molecular weight was 5.6 kDa was screened from serum using mass spectrometry technology. It was decoded to be a fragment of isoform alpha of lamina-associated polypeptide 2 (LAP2α). The survival analysis revealed that LAP2α was over-expressed in breast cancer patients and indicated poor prognosis. Materials and Methods: Immunohistochemistry (IHC) was utilized to evaluate LAP2α expression in paired primary breast tumor, metastasis of axillary lymph node and ipsilateral normal breast tissue of 29 breast cancer patients. An inhibition plasmid vector of LAP2α-small hairpin RNA (LAP2α-shRNA) was constructed and transfected into MCF-7 cells. The abilities of cell proliferation and metastasis were assessed both in vitro and in vivo. The association of LAP2α with epithelial-to-mesenchymal transition (EMT) was determined by western blot. Results: LAP2α expression of paired tissue descended in order of metastasis of axillary lymph node (21/29, 72.4%), primary breast tumor (11/29, 37.9%) and ipsilateral normal breast tissue (4/29, 13.8%) (P&lt;0.05 in comparisons between each two groups). CCK-8 experiments on transfected and control cells showed that inhibition of LAP2α could not influence cell proliferation. Transwell and matrigel-transwell assays indicated that inhibition of LAP2α could significantly reduce cell migration and invasion abilities. In vivo experiments utilizing subcutaneous xenograft model and tail vein-injection mouse model revealed that the down-regulation of LAP2α might suppress tumorigenesis and metastasis of breast cancer. Western blot suggested that down regulation of LAP2α increased the E-cadherin expression level but repressed N-cadherin and vimentin expression levels. Conclusions: A novel tumor marker candidate, LAP2α is related to metastasis of breast cancer both in clinical samples and tissue culture experiments. Inhibition of LAP2α could suppress aggressiveness and metastasis of breast cancer probably via EMT suppression. Funding: The Natural Science Foundation of Zhejiang Province of China (No. LY14H160030 and LY13H160011), the National Program on Key Basic Research Project of China (973 Program; No. 2014CB542003), the National Natural Science Foundation of China (No. 30801341) and Zheng Shu Elite Scholarship for Clinical Medicine. Citation Format: Hu Y, Qiu J, Zhou M, Li X, Huang Y. LAP2alpha, a novel tumor marker candidate is related to metastasis of breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-01-20.

CT-guided MWA is a promising treatment alternative for local tumor control in selected patients with lung metastases from NPC.