A new study shows that loss of a small RNA molecule in liver cells might cause liver cancer and that restoring the molecule might slow tumour growth and offer a new way to treat the disease.

The animal study was led by researchers at the Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).

The scientists examined what happens when liver cells lack a molecule called microRNA-122 (miR-122). They found that when the molecule is missing, the liver develops fat deposits, inflammation and tumours that resemble hepatocellular carcinoma (HCC), the most common form of liver cancer.

When the researchers artificially restored miR-122 to nearly normal levels by delivering the miR-122 gene into liver cells, it dramatically reduced the size and number of tumours, with tumours making up 8 percent on average of liver surface area in treated animals versus 40 percent in control animals.

‘These findings reveal that miR-122 has a critical tumour-suppressor role in the healthy liver, and they highlight the possible therapeutic value of miR-122 replacement for some patients with liver cancer,’ says study leader Dr. Kalpana Ghoshal, associate professor of pathology and a member of the OSUCCC – James Experimental Therapeutics Program.

More than 28,700 new cases of HCC are expected in the United States in 2012, and 20,550 Americans are expected to die of the malignancy. Major risk factors for HCC include hepatitis B and C virus infection and liver damage due to alcohol use. HCC is curable if caught early, but most cases are diagnosed at a late, incurable stage.

MiR-122 is found mainly in liver cells – it is the most abundant microRNA in those cells – and it plays a major role in regulating cholesterol in the body. This microRNA is lost in some people with HCC, however, resulting in a poor prognosis.

For this study, Ghoshal and her colleagues developed a strain of mice that lacks miR-122 and develops HCC through the progression of events that begins with fatty liver deposits followed by inflammation and liver cancer.

The researchers then used a second strain of mice that spontaneously develops liver cancer due to over-expression of a cancer-causing gene called MYC (pronounced ‘mick’). The researchers delivered miR-122 into the animals’ livers during tumour development. Three weeks later, those treated with the molecule had smaller and fewer tumours.

‘The model we developed for these studies will not only facilitate our understanding of liver biology but also be good for testing therapeutic efficacy of newly developed drugs against liver disease, including HCC,’ Ghoshal says.

Ghoshal also notes that research by others has shown that hepatitis C virus requires miR-122 for replication. ‘Because our findings demonstrate what happens when miR-122 is lost in liver cells, they might help improve the safety of new drugs that treat hepatitis C virus infection by blocking miR-122,’ she says. The Ohio State University Comprehensive Cancer Center

Blood hormone tests can predict a woman’s risk for developing postmenopausal breast cancer for up to 20 years, according to a study led by Xuehong Zhang, MD, Channing Division of Network Medicine, Brigham and Women’s Hospital (BWH) Department of Medicine.
Using data from the Nurses’ Health Study, Zhang , Susan Hankinson, ScD, Channing Division of Network Medicine, BWH Department of Medicine and colleagues analysed 796 patients with postmenopausal breast cancer who had not received hormone therapy.
They conducted blood hormone tests at two time points: between 1989 and 1990 and between 2000 and 2002. Researchers matched each patient with two controls who were not diagnosed with breast cancer.
‘We found that a single hormone level was associated with breast cancer risk for at least 16 to 20 years among postmenopausal women not using postmenopausal hormones,’ said Zhang. ‘We, and others, are now evaluating if the addition of hormone levels to current risk prediction models can substantially improve our ability to identify high-risk women who would benefit from enhanced screening or chemoprevention-if so, the current data suggest that hormone levels would not need to be measured in the clinic more than once every 10, or possibly 20, years.’
Women with hormone levels in the highest 25 percent for estradiol, testosterone and DHEAS had a 50 percent to 107 percent greater chance for developing breast cancer compared with women in the lowest 25 percent. Relative risks for developing breast cancer were similar at one to 10 years vs. 11 to 20 years (also 16 to 20 years) after blood collection.
Researchers also investigated whether these higher levels were more closely linked to hormone-receptor positive breast cancers and if they predicted risk regardless of tumour aggressiveness.
In the first case, they found that elevated levels of estradiol increase a woman’s risk for hormone receptor-positive breast cancer, specifically oestrogen receptor-positive (ER+) and progesterone receptor-positive (PR+) tumours.
In general, increased hormone levels, except for DHEAS, tracked closely with increased risk for receptor-positive breast cancer. Data on receptor-negative cancers were inconclusive and need additional, large studies.
Significantly, elevated hormone levels were also associated with aggressive breast cancer, which the study defined as recurrent or fatal cancer.
‘The relationship was comparable or possibly stronger for recurrent and fatal breast cancer than it was for overall breast cancer risk although these results were based on relative small numbers of participants,’ said Zhang.
Researchers also confirmed the protective effect of sex hormone-binding globulin (SHBG), which seems to negate the cancer-causing effects of certain hormones. Women in the highest 25 percent of SHBG levels had a 30 percent lower risk for breast cancer compared with women in the lowest 25 percent for SHBG levels.
Zhang noted that the study had low case numbers for several cancer subgroups, including HER2, triple-negative and basal-like breast cancers. More research is necessary to determine the relationship between elevated hormone levels and these important breast cancer groups. Brigham and Women’s Hospital

Lung cancer researchers at St. Joseph’s Hospital and Medical Center in Phoenix, Ariz., in collaboration with researchers at the Translational Genomics Research Institute and other institutions, have identified a gene that plays a role in the growth and spread of non-small cell lung cancer tumours, opening the door for potential new treatment options.
Landon J. Inge, PhD, is the lead scientist in the thoracic oncology laboratory at St. Joseph’s Center for Thoracic Disease and Transplantation and was a member of the study’s research team.
Lung cancer is the leading cause of cancer deaths worldwide, and approximately 85 percent of these cancers are non-small cell lung cancers (NSCLC). Patients with NSCLC frequently have tumours with mutations in the epidermal growth factor receptor (EGFR) gene. When activated, this mutated gene leads to tumour development and growth. By studying lung cancer samples from patients who had undergone tumour resection, the researchers discovered that many patients with EGFR mutations also exhibited higher than normal levels of the gene fibroblast growth factor-inducible 14 (Fn14). The researchers believe that activation of EGFR can lead to increased expression and activity of the Fn14 gene.
The research team also discovered that while over-expression of Fn14 enhances lung tumour formation and metastasis, suppression of Fn14 reduces metastasis in NSCLC.
‘Our data suggest that Fn14 levels can contribute to NSCLC cell migration and invasion,’ says Dr. Inge. ‘Thus, tumour suppression through the targeting of Fn14 may prove to be a therapeutic intervention in NSCLC and other tumour types.’
The Fn14 gene has been found to be elevated in other types of tumours, as well, including glioblastoma and certain types of breast cancer, suggesting that Fn14 may be a therapeutic target for multiple cancer therapies. EurekAlert

Researchers for the first time have shown that members of a family of enzymes known as cathepsins – which are implicated in many disease processes – may attack one another instead of the bodily proteins they normally degrade. Dubbed ‘cathepsin cannibalism,’ the phenomenon may help explain problems with drugs that have been developed to inhibit the effects of these powerful proteases.
Cathepsins are involved in disease processes as varied as cancer metastasis, atherosclerosis, cardiovascular disease, osteoporosis and arthritis. Because cathepsins have harmful effects on critical proteins such as collagen and elastin, pharmaceutical companies have been developing drugs to inhibit activity of the enzymes, but so far these compounds have had too many side effects to be useful and have failed clinical trials.
Using a combination of modelling and experiments, researchers from the Georgia Institute of Technology and Emory University have shown that one type of cathepsin preferentially attacks another, reducing the enzyme’s degradation of collagen. The work could affect not only the development of drugs to inhibit cathepsin activity, but could also lead to a better understanding of how the enzymes work together.
‘These findings provide a new way of thinking about how these proteases are working with and against each other to remodel tissue – or fight against each other,’ said Manu Platt, an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. ‘There has been an assumption that these cathepsins have been inert in relationship to one another, when in actuality they have been attacking one another. We think this may have broader implications for other classes of proteases.’
Platt and student Zachary Barry made their discovery accidentally while investigating the effects of cathepsin K and cathepsin S – two of the 11-member cathepsin family. Cathepsin K degrades both collagen and elastin, and is one of the most powerful proteases. Cathepsin S degrades elastin, and does not strongly attack collagen.
When the researchers combined the two cathepsins and allowed them to attack samples of elastin, they expected to see increased degradation of the protein. What they saw, however, was not much more damage than cathepsin K did by itself.
Platt at first believed the experiment was flawed, and asked Barry – an undergraduate student in his lab who specialises in modelling – to examine what possible conditions could account for the experimental result. Barry’s modelling suggested that effects observed could occur if cathepsin S were degrading cathepsin K instead of attacking the elastin – a protein essential in arteries and the cardiovascular system.
That theoretical result led to additional experiments in which the researchers measured a direct correlation between an increase in the amount of cathepsin S added to the experiment and a reduction in the degradation of collagen. By increasing the amount of cathepsin S ten-fold over the amount used in the original experiment, Platt and Barry were able to completely block the activity of cathepsin K, preventing damage to the collagen sample.
‘We saw that the cathepsin K was going away much faster when there was cathepsin S present than when it was by itself,’ said Platt, who is also a Georgia Cancer Coalition Distinguished Scholar and a Fellow of the Keystone Symposia on Molecular and Cellular Biology. ‘We kept increasing the amount of cathepsin S until the collagen was not affected at all because all of the cathepsin K was eaten by the cathepsin S.’
The researchers used a variety of tests to determine the amount of each enzyme, including fluorogenic substrate analysis, Western blotting and multiplex cathepsin zymography – a sensitive technique developed in the Platt laboratory.
Beyond demonstrating for the first time that cathepsins can attack one another, the research also shows the complexity of the body’s enzyme system – and may suggest why drugs designed to inhibit cathepsins haven’t worked as intended.
‘The effect of the cathepsins on one another complicates the system,’ said Platt. ‘If you are targeting this system pharmaceutically, you may not have the types or quantities of cathepsins that you expect, which could cause off- Georgia Institute of Technology Research News

Perhaps variety is the very spice of life, but as a matter of producing human life, it could be the bane of existence. That’s the indication of a new study that found men with wider variation in sperm length, particularly in the flagellum, had lower concentrations of sperm that could swim well. Those with more consistently made sperm seemed to have more capable ones.
‘Our study reveals that men who produce higher concentrations of competent swimming sperm also demonstrate less variation in the size and shape of those sperm,’ said Jim Mossman, a postdoctoral scholar at Brown University and lead author of the paper. ‘It suggests that in some cases, testes are working more optimally to produce high numbers of consistently manufactured sperm, and vice versa.’
At the University of Sheffield, where Mossman did his doctoral studies, he and his co-authors measured the heads, midpieces, and flagella of 30 sperm per man, from 103 men randomly selected from a pool of about 500 who were recruited for a larger fertility study. They also measured other characteristics of each man’s semen, such as sperm concentration and motility, that the World Health Organisation recognises as important markers of fertility.
‘The WHO suggests that measurements should be made on multiple components of sperm, but generally it’s only the sperm head that is considered,’ Mossman said. ‘No one’s ever looked at this before across sperm components. What we show is that measurements on other sperm parts, such as the flagellum that propels the sperm, can provide additional information about the quality and consistency of sperm manufacture.’
The result of the novel analysis yielded two overall findings. One was that men who had higher mean flagellum length, total sperm length, and flagellum-to-head length ratios had higher concentrations of motile sperm. But perhaps the more interesting finding was that the greater the inconsistency of length in the sperm a man manufactures, particularly with regard to the flagellum, the lower his concentration of sperm that could swim well.
‘The finding could give clinicians new insight into the diagnosis and treatment of male fertility problems, which accounts for up to 50 percent of the cases where couples struggle to conceive,’ Mossman said. The research suggests that at least in some men, measurable inconsistency in sperm length may be a sign of trouble with his process of making sperm, a process known as spermatogenesis. That trouble, akin to a manufacturing line with poor quality control, could result in a lower concentration of good swimmers. Brown University