CA : A Cancer Journal for Clinicians

Introduction 
The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals.


Materials and Methods 
A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed.


Results 
None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR-145 correlated with nadir CD4+ T cell count.


Discussion 
No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection.

/pdf/circulating-micrornas-in-sera-correlate-with-soluble-4z0esjrm8u.pdf

Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection : a case control study

EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.

Hypertension 66 (20.3%) 24 (24.2%) 30 (16.3%) NS Diabetes 20 (6.2%) 7 (7.1%) 10 (5.4%) NS Excess weight 78 (24%) 27 (27.3%) 44 (23.9%) NS Smokers 64 (19.7%) 17 (17.2%) 35 (19.0%) NS Age >50 years 137 (42.2%) 54 (54.5%) 67 (36.4%) <0.02 Kidney disease 7 (2.2%) 1 (1%) 5 (2.7%) NS Family history, DM 102 (31.4%) 28 (28.3%) 66 (35.9%) NS

Conflict of interest statement. None declared.

Most RNAs generated by the human genome have no protein-coding ability and are termed non-coding RNAs. Among these include circular RNAs, which include exonic circular RNAs (circRNA), mainly found in the cytoplasm, and intronic RNAs (ciRNA), predominantly detected in the nucleus. The biological functions of circular RNAs remain largely unknown, although ciRNAs have been reported to promote gene transcription, while circRNAs may function as microRNA sponges. We demonstrate that the circular RNA circ-Foxo3 was highly expressed in non-cancer cells and were associated with cell cycle progression. Silencing endogenous circ-Foxo3 promoted cell proliferation. Ectopic expression of circ-Foxo3 repressed cell cycle progression by binding to the cell cycle proteins cyclin-dependent kinase 2 (also known as cell division protein kinase 2 or CDK2) and cyclin-dependent kinase inhibitor 1 (or p21), resulting in the formation of a ternary complex. Normally, CDK2 interacts with cyclin A and cyclin E to facilitate cell cycle entry, while p21works to inhibit these interactions and arrest cell cycle progression. The formation of this circ-Foxo3-p21-CDK2 ternary complex arrested the function of CDK2 and blocked cell cycle progression.

/pdf/foxo3-circular-rna-retards-cell-cycle-progression-via-4l25l8xmr1.pdf

Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2

Background and Aim: Circulating miRNAs exist in serum and plasma and they can be used as a potential noninvasive molecular marker for colorectal cancer (CRC) diagnosis. The present study was to test the availability of direct amplification of miRNAs from plasma without RNA extraction, and to evaluate its clinical application value in CRC. Methods: Plasma miR-21, miR-221 and miR-222 levels were determined in 103 CRC patients and 37 healthy normal controls by quantitative reverse transcription-polymerase chain reaction. Immunohistochemical staining for p53, carcinoembryonic antigen (CEA), estrogen receptor (ER) and progesterone receptor (PR) was carried out in the same CRC patient cohort. The correlation between miR-221 levels and protein levels of p53, CEA, ER and PR, clinicopathological features or overall survival was analyzed. Results: A standard curve shows a good linearity between the log of sample input and CT values over three orders of magnitude of plasma miR-21, miR-221 and miR-222. ROC curve analysis reveals that the plasma levels of miR-221 is a potential biomarker for differentiating CRC patients from controls. Kaplan-Meier curve assessment shows that the elevated plasma miR-221 level is a significant prognostic factor for poor overall survival in CRC patients. The immunohistochemistry analysis demonstrates a significant correlation between plasma miR-221 level and p53 expression. Conclusions: The direct amplification of plasma miR-221 can be used as a potential noninvasive molecular marker for diagnosis and prognosis of CRC and is correlated with p53 expression.

Circulating miR-221 directly amplified from plasma is a potential diagnostic and prognostic marker of colorectal cancer and is correlated with p53 expression

Experimental investigation of thermal conductivity and viscosity of ethylene glycol based ZnO nanofluids

// Lekun Fang 1,* , Haoran Li 2,4,* , Lei Wang 1 , Jun Hu 1 , Tianru Jin 3 , Jianping Wang 1 , Burton B Yang 2,4 1 Guangdong Gastroenterology Institute, The Sixth Affiliated Hospital of Sun Yat-sen University,  China 2 Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto 3 University Health Network, Toronto, Canada 4 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto * These authors contributed equally Correspondence: J Wang, email: // BB Yang, email: // Keywords : microRNA, stem cell, miR-17, colon cancer, drug resistance Received : November 19, 2013 Accepted : January 19, 2014 Published : January 19, 2014 Abstract Background: Colorectal cancer (CRC) is one of the most common cancers worldwide, especially in Western countries. Although chemotherapy is used as an adjuvant or as a palliative treatment, drug resistance poses a great challenge. This study intended to identify biomarkers as predictive factors for chemotherapy. Patients and methods: By microarray analysis, we studied miRNAs expression profiles in CRC patient, comparing chemoresistant and chemosensitive groups. The miRNAs of interest were validated and the impact on clinical outcomes was assessed in a cohort of 295 patients. To search for potential targets of these miRNAs, tissue samples were subject to in situ hybridization and immunohistochemistry analysis. Colorectal adenocarcinoma cells were also used for in vitro experimentation, where cellular invasiveness and drug resistance were examined in miRNA-transfected cells. Results: The expression level of miRNA-17-5p was found increased in chemoresistant patients. Significantly higher expression levels of miR-17-5p were found in CRC patients with distant metastases and higher clinical stages. Kaplan-Meier analysis showed that CRC patients with higher levels of miR-17-5p had reduced survival, especially in patients who had previously received chemotherapy. Overexpression of miR-17-5p promoted COLO205 cell invasiveness. We found that PTEN was a target of miR-17-5p in the colon cancer cells, and their context-specific interactions were responsible for multiple drug-resistance. Chemotherapy was found to increase the expression levels of miR-17-5p, which further repressed PTEN levels, contributing to the development of chemo-resistance. Conclusions: MiR-17-5p is a predictive factor for chemotherapy response and a prognostic factor for overall survival in CRC, which is due to its regulation of PTEN expression.

/pdf/microrna-17-5p-promotes-chemotherapeutic-drug-resistance-and-3wbvd6fbw8.pdf

MicroRNA-17-5p promotes chemotherapeutic drug resistance and tumour metastasis of colorectal cancer by repressing PTEN expression

MicroRNAs (miRNA) precursor (pre-miRNA) molecules can be processed to release a miRNA/miRNA* duplex. In the canonical model of miRNA biogenesis, one strand of the duplex is thought to be the biologically active miRNA, whereas the other strand is thought to be inactive and degraded as a carrier or passenger strand called miRNA* (miRNA star). However, recent studies have revealed that miRNA* strands frequently play roles in the regulatory networks of miRNA target molecules. Our recent study indicated that miR-17 transgenic mice could abundantly express both the mature miR-17-5p and the passenger strand miR-17-3p. Here, we showed that miR-17 enhanced prostate tumor growth and invasion by increasing tumor cell proliferation, colony formation, cell survival and invasion. miRNA target analysis showed that both miR-17-5p and miR-17-3p repressed TIMP metallopeptidase inhibitor 3 (TIMP3) expression. Silencing with small interfering RNA against TIMP3 promoted cell survival and invasion. Ectopic expression of TIMP3 decreased cell invasion and cell survival. Our results demonstrated that mature miRNA can function coordinately with its passenger strand, enhancing the repressive ability of a miRNA by binding the same target. Within an intricate regulatory network, this may be among the mechanisms by which miRNA can augment their regulatory capacity.

/pdf/both-mature-mir-17-5p-and-passenger-strand-mir-17-3p-target-4hnugltgp6.pdf

Both mature miR-17-5p and passenger strand miR-17-3p target TIMP3 and induce prostate tumor growth and invasion

Here we report that miR-93, a miRNA in the miR-106B~25 cluster, a paralog of the miR-17–92 cluster, was significantly upregulated in human breast carcinoma tissues. We stably expressed miR-93 in the MT-1 human breast carcinoma cell line and found that tumors formed by the miR-93 cells contained more blood vessels than those formed by the control cells. Co-culture experiments indicated that the MT-1 cells displayed a high activity of adhesion with endothelial cells and could form larger and more tube-like structures with endothelial cells. Lung metastasis assays were performed in a mouse metastatic model, and it was found that expression of miR-93 promoted tumor cell metastasis to lung tissue. In cell culture, expression of miR-93 enhanced cell survival and invasion. We examined the potential target that mediated miR-93’s effects and found that the large tumor suppressor, homology 2 (LATS2) was a target of miR-93. Higher levels of LATS2 were associated with cell death in the tumor mass. Silencing LATS2 expression promoted cell survival, tube formation and invasion, while ectopic expression of LATS2 decreased cell survival and invasion. These findings demonstrated that miR-93 promoted tumor angiogenesis and metastasis by suppressing LATS2 expression. Our results suggest that the inhibition of miR-93 function may be a feasible approach to repress tumor metastasis.

Haoran Li

Papers

Circulating miR-221 directly amplified from plasma is a potential diagnostic and prognostic marker of colorectal cancer and is correlated with p53 expression

Experimental investigation of thermal conductivity and viscosity of ethylene glycol based ZnO nanofluids

MicroRNA-17-5p promotes chemotherapeutic drug resistance and tumour metastasis of colorectal cancer by repressing PTEN expression

Both mature miR-17-5p and passenger strand miR-17-3p target TIMP3 and induce prostate tumor growth and invasion

MiR-93 enhances angiogenesis and metastasis by targeting LATS2