Cornell researchers report they have discovered direct genetic evidence that a family of genes, called MicroRNA-34 (miR-34), are bona fide tumour suppressors.
Previous research at Cornell and elsewhere has shown that another gene, called p53, acts to positively regulate miR-34. Mutations of p53 have been implicated in half of all cancers. Interestingly, miR-34 is also frequently silenced by mechanisms other than p53 in many cancers, including those with p53 mutations.
The researchers showed in mice how interplay between genes p53 and miR-34 jointly inhibits another cancer-causing gene called MET. In absence of p53 and miR-34, MET overexpresses a receptor protein and promotes unregulated cell growth and metastasis.
This is the first time this mechanism has been proven in a mouse model, said Alexander Nikitin, a professor of pathology in Cornell’s Department of Biomedical Sciences and the paper’s senior author. Chieh-Yang Cheng, a graduate student in Nikitin’s lab, is the paper’s first author.
In a 2011 Proceedings of the National Academy of Sciences paper, Nikitin and colleagues showed that p53 and miR-34 jointly regulate MET in cell culture but it remained unknown if the same mechanism works in a mouse model of cancer (a special strain of mice used to study human disease).
The findings suggest that drug therapies that target and suppress MET could be especially successful in cancers where both p53 and miR-34 are deficient.
The researchers used mice bred to develop prostate cancer, then inactivated the p53 gene by itself, or miR-34 by itself, or both together, but only in epithelium tissue of the prostate, as global silencing of these genes may have produced misleading results.
When miR-34 genes alone were silenced in the mice, the mice developed cancer free. When p53 was silenced by itself, there were signs of precancerous lesions early in development, but no cancer by 15 months of age. When miR-34 and p53 genes were both silenced together, the researchers observed full prostate cancer in the mice.
The findings revealed that ‘miR-34 can be a tumour-suppressor gene, but it has to work together with p53,’ Nikitin said.
In mice that had both miR-34 and p53 silenced concurrently, cancerous lesions formed in a proximal part of the prostrate ducts, in a compartment known to contain prostate stem cells. The early lesions that developed when p53 was silenced alone occurred in a distal part of the ducts, away from the compartment where the stem cell pool is located. This suggested there was another mechanism involved when p53 and miR-34 were jointly silenced.
Also, the number of stem cells in mice with both p53 and miR-34 silenced increased substantially compared with control mice or mice with only miR-34 or p53 independently silenced.
‘These results indicated that together [miR-34 and p53] regulate the prostate stem cell compartments,’ said Nikitin.
This is significant, as cancer frequently develops when stem cells become unregulated and grow uncontrollably, he said.
Researchers further found that p53 and miR-34 affect stem cell growth by regulating MET expression. In absence of p53 and miR-34, MET is overexpressed, which leads to uncontrolled growth of prostate stem cells and high levels of cancer in these mice.
Future work will further examine the role of p53/miR-34/MET genes in stem cell growth and cancer. The findings have implications for many types of cancer. Cornell University

Chinese researchers from Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, BGI, and other institutions have discovered that the activating hotspot L205R mutation in PRKACA gene was closely associated with adrenocortical tumours (ACTs), and the relationship of recurrently mutated DOT1L and CLASP2 with ACTs’ other subtypes. The latest study opens a new insight into diagnosis and treatment of Adrenal Cushing’s syndrome.

Adrenal Cushing’s syndrome results from autonomous production of cortisol (ACTH-independent) from adrenocortical tumours (ACTs), which may lead to a series of metabolic disorders such as obesity, glucose intolerance and hypertension. However, the genetic architecture of Adrenal Cushing’s syndrome remains largely uncharacterised, hampering the development of diagnostic and therapeutic approaches for Cushing’s syndrome.
In this study, researchers performed whole-exome sequencing of 49 blood-tumour pairs and RNA sequencing of 44 tumours from cortisol-producing adrenocortical adenomas (ACAs), ACTH-independent macronodular adrenocortical hyperplasia (AIMAH), and adrenocortical oncocytoma (ADO). They found there was a hotspot L205R mutation in PRKACA gene, and two novel mutated genes that have never been reported: One is DOT1L, which may contribute the tumorigenesis of AIMAH; the other is HDAC9, which would be responsible for ADOs.

In the large-scale validation stage, researchers found that L205R mutation was only found in the ACTs, and located in the highly conserved functional domain-P+1 loop of PKA catalytic subunit-plays an important role in the combination of kinase and substrate. The further molecular and cell function validation proved that L205R mutation caused the increase of protein activity and enhanced the catalytic capability of the phosphorylation, and promoted the occurrence of tumour and the production of steroid by substrate phosphorylation.

Yanan Cao, Endocrinologist from Rui-Jin Hospital, said,’ACTs and Cushing’s syndrome belong to one important kind of diseases in endocrine metabolic disorders. Our study revealed several key mutated genes closely associated with adrenocortical tumours. Furthermore, we systematically analysed the function of L205R mutation by structure and molecular biology technologies, laying a solid foundation for developing new treatment strategies for Adrenal Cushing’s syndrome.’ BGI Shenzhen

The Quo-Lab HbA1c point-of-care analyser has successfully achieved International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) certification. The IFCC maintains the JCTLM (Joint Committee for Traceability in Laboratory Medicine) endorsed reference measurement procedure for HbA1c, accepted worldwide as the analytical control for traceability of HbA1c measurement. To participate in the programme manufacturers are required to register and report the results of 24 samples (two per month) from across the measurement range. The samples are supplied by an IFCC Reference Laboratory. Together with the existing NGSP certification achieved from 2012, the IFCC award demonstrates that Quo-Lab meets all of the demanding standards set by independent certifying bodies.  

New research provides direct evidence that genetic variations in some African Americans with chronic kidney disease contribute to a more rapid decline in kidney function compared with white Americans. The research, led by investigators from the University of Maryland School of Medicine and Johns Hopkins University, may help explain, in part, why even after accounting for differences in socio-economic background, end-stage kidney disease is twice as prevalent among blacks as whites.
‘What we found is pretty remarkable — that variations in a single gene account for a large part of the racial disparity in kidney disease progression and risk for end-stage kidney disease,’ says co-lead author and nephrologist Afshin Parsa, M.D., M.P.H., assistant professor of medicine and member of the Program in Personalized and Genomic Medicine at the University of Maryland School of Medicine. ‘If it were possible to reduce the effect of this gene, there could be a very meaningful decrease in progressive kidney and end-stage kidney disease within blacks.’
Previous landmark discoveries revealed that two common variants within a gene called apolipoprotein L1 (APOL1) were strongly associated with non-diabetic end-stage renal disease in blacks. Having only one copy of the variant APOL1 gene variant is associated with a health benefit – protection against African sleeping sickness, a potentially lethal parasitic infection transmitted by the tsetse fly, found only in sub-Saharan Africa. However, people with two copies of the variant are at a higher risk for kidney disease.
The current research expands on these prior findings and demonstrates the effect of these variants on the progression of established kidney disease and development of end-stage renal disease; analyses their role in black-versus-white renal disease disparities; investigates their effect in patients with diabetes and observes the impact of blood pressure control on APOL1-associated disease progression.
According to Dr. Parsa, approximately 13 percent of the African American population has two copies of the risk variants. Fortunately, most of those at risk do not develop kidney disease. The researchers analysed the role of APOL1 gene variants in two longitudinal studies of patients with kidney disease: the Chronic Renal Insufficiency Cohort (CRIC) and the African American Study of Kidney Disease and Hypertension (AASK), both sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health (NIH). Dr. Parsa examined the CRIC study data, while co-lead author and Johns Hopkins epidemiologist W.H. Linda Kao, Ph.D., M.H.S., analysed the AASK data. University of Maryland Medical Center

Harvard stem cell scientists have identified a mutation in human cases of acute lymphoblastic leukaemia that likely drives relapse. The research could translate into improved patient care strategies for this particular blood cancer, which typically affects children but is more deadly in adults.

In recent years, a trend toward single-cell analysis has shown that individual cells within a tumour are capable of amassing mutations to make them more aggressive and treatment resistant. So while 99% of a tumour may be destroyed by the initial treatment, a particularly aggressive cell can survive and then cause a cancer patient with the ‘all clear’ to relapse six months later.

Harvard Stem Cell Institute Principal Faculty member David Langenau, PhD, and his lab members in the Department of Pathology at Massachusetts General Hospital used zebrafish to search for these rare, relapse-driving leukaemia cells and then designed therapies that could kill these cells.

The researchers found that at least half of relapse-driving leukemic cells had a mutation that activated the Akt pathway, which rendered cells resistant to common chemotherapy and increased growth. From that insight, Langenau’s lab next examined human acute lymphoblastic leukaemia and discovered that inhibition of the Akt pathway restored leukemic cell responses to front-line chemotherapy.

‘The Akt pathway appears to be a major driver of treatment resistance,’ Langenau said. ‘We also show that this same pathway increases overall growth of leukemic cells and increases the fraction of cells capable of driving relapse.’

Jessica Blackburn, PhD, the study’s first author adds, ‘Our work will likely help in identifying patients that are prone to relapse and would benefit from co-treatment with inhibitors of the Akt pathway and typical front-line cancer therapy.’

In addition to determining how best to translate this finding into the clinic, Langenau hopes to identify other mutations that lead to relapse. The work should identify a host of other potential drug targets for patients with aggressive leukaemia. Harvard Stem Cell Institute