Molecule critical to healing wounds identified

Nov. 15, 2013 — Skin provides a first line of defense against viruses, bacteria and parasites that might otherwise make people ill. When an injury breaks that barrier, a systematic chain of molecular signaling launches to close the wound and re-establish the skin's layer of protection.

A study led by researchers from the University of Pennsylvania's School of Dental Medicine and published in the Journal of Cell Biology now offers a clearer explanation of the role of one of the players in the wound-healing process, a molecule called FOX01. Contrary to what had been expected, FOX01 is critical to wound healing, providing researchers with a possible new target for drugs that could help speed that process for people with impaired wound healing.

Senior author Dana Graves is a professor in Penn Dental Medicine's Department of Periodontics and is vice dean for scholarship and research. He collaborated on the study with Penn's Bhaskar Ponugoti, Fanxing Xu, Chenying Zhang, Chen Tian and Sandra Pacio.

A critical element of wound healing involves the movement of keratinocytes, the primary cells comprising the epidermis, or the outer layer of skin. Previous research had found that FOX01 was expressed at higher levels in wounds, but scientists did not understand what role the molecule was playing. In other scenarios, such as in cancer cells, FOX01 promotes cell death and interferes with the cell reproduction, two actions that would seem to be detrimental to healing.

To investigate the role of FOX01 in wound healing, Graves and colleagues bred mice that lacked the protein in their keratinocytes and then observed the wound healing process in these mice compared to mice with normal FOX01.

"We thought that deleting FOX01 would speed up the wound-healing process," Graves said, "but in fact it had the opposite effect."

The mice that lacked FOX01 showed significant delays in healing. Whereas all wounds on control mice were healed after one week, all of the experimental mice still had open wounds.

Digging deeper into this counterintuitive finding, the researchers examined the effect of reducing FOX01 levels on other genes known to play a role in cell migration. They found that many of these genes were significantly reduced, notably TGF-β1, a critical growth factor in wound repair. When the team added TGF-β1 to cells lacking FOX01, the cells behaved normally and produced the proper suite of molecules needed for healing, indicating that FOX01 acts upstream of TGF-β1 in the signaling pathway triggered during the healing process.

Further experimenting revealed that mice lacking FOX01 had evidence of increased oxidative stress, which is detrimental to wound healing.

"The wound healing environment is a stressful environment for the cell," Graves said. "It appears that upregulation of FOX01 helps protect the cell against oxidative stress."

The fact that FOX01 behaves in this unexpected way could have to do with the specialized microenvironment of a cell in a wound, Graves noted. While FOX01 does indeed promote cell death when it is highly activated, it does the opposite when moderately activated. Which activity it promotes depends on the environment in which it is acting.

Taken together, the study's findings demonstrate that FOX01 plays an integral role in two key processes in wound healing: activation of TGF-β1 and protecting the cell against oxidative damage. Its involvement in these aspects of healing make it a potential target for pharmaceuticals that could help speed healing.

"If you had a small molecule that increased FOX01 expression, you might be able to upregulate TGF-β1 as well as protect against the oxidative stress associated with wound healing," Graves said.

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Proteins identified that may help brain tumors spread

Sep. 20, 2013 — Scientists at the University of Alabama at Birmingham have identified a molecular pathway that seems to contribute to the ability of malignant glioma cells in a brain tumor to spread and invade previously healthy brain tissue. Researchers said the findings, published Sept. 19, 2013, in the journal PLOS ONE, provide new drug-discovery targets to rein in the ability of these cells to move.

Gliomas account for about a third of brain tumors, and survival rates are poor; only about half of the 10,000 Americans diagnosed with malignant glioma survive the first year, and only about one quarter survive for two years.

“Malignant gliomas are notorious, not only because of their resistance to conventional chemotherapy and radiation therapy, but also for their ability to invade the surrounding brain, thus causing neurological impairment and death,” said Hassan Fathallah-Shaykh, M.D., Ph.D., associate professor in the UAB Department of Neurology. “Brain invasion, a hallmark of gliomas, also helps glioma cells evade therapeutic strategies.”

Fathallah-Shaykh said there is a great deal of interest among scientists in the idea that a low-oxygen environment induces glioma cells to react with aggressive movement, migration and brain invasion. A relatively new cancer strategy to shrink tumors is to cut off the tumor’s blood supply – and thus its oxygen source – through the use of anti-angiogenesis drugs. Angiogenesis is the process of making new blood vessels.

“Stop angiogenesis and you shut off a tumor’s blood and oxygen supply, denying it the components it needs to grow,” said Fathallah-Shaykh. “Drugs that stop angiogenesis are believed to create a kind of killing field. This study identified four glioma cell lines that dramatically increased their motility when subjected to a low-oxygen environment – in effect escaping the killing field to create a new colony elsewhere in the brain.”

Fathallah-Shaykh and his team then identified two proteins that form a pathway linking low oxygen, or hypoxia, to increased motility.

“We identified a signaling protein that is activated by hypoxia called Src,” said Fathallah-Shaykh. “We also identified a downstream protein called neural Wiskott-Aldrich syndrome protein (N-WASP), which is regulated by Src in the cell lines with increased motility.”

The researchers then used protein inhibitors to shut off Src and N-WASP. When either protein was inhibited, low oxygen lost its ability to augment cell movement.

“These findings indicate that Src, N-WASP and the linkage between them – which is something we don’t fully understand yet – are key targets for drugs that would interfere with the ability of a cell to move.” said Fathallah-Shaykh. “If we can stop them from moving, then techniques such as anti-angiogenesis should be much more effective. Anti-motility drugs could be a key component in treating gliomas in the years to come.”

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Protein identified that regulates cellular trafficking, potential for anti-cancer therapy

Sep. 22, 2013 — Molecular microbiologists at the University of Southern California (USC) have uncovered intricate regulatory mechanisms within the cell that could lead to novel therapeutics for the treatment of cancer and other diseases. Their findings, which have long-standing significance in the basic understanding of cell biology, appear in the journal Nature Cell Biology.

"Our research reveals a new regulatory mechanism that coordinates two distinct intracellular processes that are critical to cellular homeostasis and disease development," said Chengyu Liang, M.D., Ph.D., a member of the USC Norris Comprehensive Cancer Center and principal investigator of the study.

The endoplasmic reticulum (ER) and Golgi apparatus are cellular organelles in eurkaryotic organisms where proteins are synthesized and packaged for secretion through the body. The trafficking of proteins between the ER and Golgi must be tightly modulated to maintain the health of the cell and prevent diseases like cancer from taking hold.

"Interest in the role of ER-Golgi network during cancer cell death has been gaining momentum," said Shanshan He, Ph.D., research associate at the Keck School of Medicine of USC and one of the study's first authors. "In this study, we identified a novel regulatory factor for the Golgi-ER retrograde transport and a new mechanistic connection between the physiological trafficking and the autophagic transportation of cellular material."

The researchers discovered that the UV irradiation resistance-associated gene protein (UVRAG), which has been implicated in the suppression of colon and breast cancer, coordinates trafficking of proteins between the ER and Golgi apparatus and also autophagy, the natural process of breaking down cellular components.

"Given that the ER-Golgi network is often dismantled in malignant conditions and that UVRAG is intensively involved in different types of human cancers, this study gives us a new avenue to investigate anti-cancer agents that target UVRAG and/or the ER-Golgi pathway in cancer and other relevant diseases," Liang said.

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Protein identified that regulates cellular trafficking, potential for anti-cancer therapy

Sep. 22, 2013 — Molecular microbiologists at the University of Southern California (USC) have uncovered intricate regulatory mechanisms within the cell that could lead to novel therapeutics for the treatment of cancer and other diseases. Their findings, which have long-standing significance in the basic understanding of cell biology, appear in the journal Nature Cell Biology.

"Our research reveals a new regulatory mechanism that coordinates two distinct intracellular processes that are critical to cellular homeostasis and disease development," said Chengyu Liang, M.D., Ph.D., a member of the USC Norris Comprehensive Cancer Center and principal investigator of the study.

The endoplasmic reticulum (ER) and Golgi apparatus are cellular organelles in eurkaryotic organisms where proteins are synthesized and packaged for secretion through the body. The trafficking of proteins between the ER and Golgi must be tightly modulated to maintain the health of the cell and prevent diseases like cancer from taking hold.

"Interest in the role of ER-Golgi network during cancer cell death has been gaining momentum," said Shanshan He, Ph.D., research associate at the Keck School of Medicine of USC and one of the study's first authors. "In this study, we identified a novel regulatory factor for the Golgi-ER retrograde transport and a new mechanistic connection between the physiological trafficking and the autophagic transportation of cellular material."

The researchers discovered that the UV irradiation resistance-associated gene protein (UVRAG), which has been implicated in the suppression of colon and breast cancer, coordinates trafficking of proteins between the ER and Golgi apparatus and also autophagy, the natural process of breaking down cellular components.

"Given that the ER-Golgi network is often dismantled in malignant conditions and that UVRAG is intensively involved in different types of human cancers, this study gives us a new avenue to investigate anti-cancer agents that target UVRAG and/or the ER-Golgi pathway in cancer and other relevant diseases," Liang said.

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New marker identified for early diagnosis of lung cancer

Sep. 17, 2013 — A protein called isocitrate dehydrogenase (IDH1) is present at high levels in lung cancers and can be detected in the blood, making it a noninvasive diagnostic marker for lung cancers, according to a study published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

"This study is the first to report identification of IDH1 as a novel biomarker for the diagnosis of non-small cell lung cancers (NSCLC) using a large number of clinical samples," said Jie He, M.D., Ph.D., director of the Laboratory of Thoracic Surgery at the Peking Union Medical College and Chinese Academy of Medical Sciences in Beijing. "Lung cancer has a high mortality rate, mostly because of late diagnosis. With an increase in aging population, we are likely to see an increase in lung cancer incidence and a need for better biomarkers for early diagnosis. We have identified IDH1 as an effective plasma biomarker with high sensitivity and specificity in the diagnosis of NSCLC, especially lung adenocarcinoma."

Lung cancer is the leading cause of cancer deaths in both men and women in the United States and worldwide. To detect lung cancer in blood, currently certain biomarkers including CEA, Cyfra21-1 and CA125 are used, but these markers are not very sensitive, according to He.

He and colleagues found that IDH1 could be detected in the blood of lung cancer patients with 76 percent sensitivity and 77 percent specificity. When they used a mathematical model to combine the detection of IDH1 with the detection of existing markers CEA, Cyfra21-1, and CA125, the sensitivity increased to 86 percent.

"Based on the present data, IDH1 can be used to detect stage 1 lung cancer; however, it is also possible that IDH1 could be used to detect precancer but further studies are required to address that possibility," said He.

He and colleagues used blood samples collected from 943 patients with NSCLC and 479 healthy controls, enrolled between 2007 and 2011 in the Cancer Institute and Hospital of the Chinese Academy of Medical Sciences. None of the study participants had a cancer diagnosis, nor were they treated for cancer in the three years prior to the study. Using methods called ELISA and ECL, they measured the levels of IDH1, CEA, Cyfra21-1, and CA125 in the participants' blood.

The researchers then divided the samples into a training set and a test set to validate the detection efficiency of IDH1. They found the data obtained from the test set were as good as those from the training set, demonstrating the robustness of IDH1 as a biomarker for lung cancer diagnosis.

The median IDH1 levels in patients with two types of lung cancer, adenocarcinoma and squamous cell carcinoma, were 2.7-fold and 2.2-fold higher, respectively, compared with healthy controls.

The researchers also found that combining the detection of all four markers -- IDH1, CEA, Cyfra21-1, and CA125 -- helped to better classify different types of adenocarcinoma, compared with detection with IDH1 alone.

He and colleagues are planning to conduct a multicenter clinical trial for further validation of IDH1.

"Our research also suggests IDH1 may be involved in the development of lung cancer, and it may be a good target for the treatment of NSCLC," said He. His team is currently studying the molecular mechanisms that increase IDH1 in lung cancer patients and its clinical implications.

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Genes linked to being right- or left-handed identified

Sep. 12, 2013 — A genetic study has identified a biological process that influences whether we are right handed or left handed.

Scientists at the Universities of Oxford, St Andrews, Bristol and the Max Plank Institute in Nijmegen, the Netherlands, found correlations between handedness and a network of genes involved in establishing left-right asymmetry in developing embryos.

'The genes are involved in the biological process through which an early embryo moves on from being a round ball of cells and becomes a growing organism with an established left and right side,' explained first author William Brandler, a PhD student in the MRC Functional Genomics Unit at Oxford University.

The researchers suggest that the genes may also help establish left-right differences in the brain, which in turn influences handedness.

They report their findings in the open-access journal PLOS Genetics.

Humans are the only species to show such a strong bias in handedness, with around 90% of people being right-handed. The cause of this bias remains largely a mystery.

The researchers, led by Dr Silvia Paracchini at the University of St Andrews, were interested in understanding which genes might have an influence on handedness, in order to gain an insight into the causes and evolution of handedness.

The team carried out a genome-wide association study to identify any common gene variants that might correlate with which hand people prefer using.

The most strongly associated, statistically significant variant with handedness is located in the gene PCSK6, which is involved in the early establishment of left and right in the growing embryo.

The researchers then made full use of knowledge from previous studies of what PCSK6 and similar genes do in mice to reveal more about the biological processes involved.

Disrupting PCSK6 in mice causes 'left-right asymmetry' defects, such as abnormal positioning of organs in the body. They might have a heart and stomach on the right and their liver on the left, for example.

The researchers found that variants in other genes known to cause left-right defects when disrupted in mice were more likely to be associated with relative hand skill than you would expect by chance.

While the team has identified a role for genes involved in establishing left from right in embryo development, William Brandler cautioned that these results do not completely explain the variation in handedness seen among humans. He said: 'As with all aspects of human behaviour, nature and nurture go hand-in-hand. The development of handedness derives from a mixture of genes, environment, and cultural pressure to conform to right-handedness.'

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New mutation identified, associated with better survival in lung cancer patients

Sep. 12, 2013 — Japanese researchers have identified a mutation associated with a higher incidence of lung cancer in Japanese women who do not smoke, but better survival in lung cancer patients. In a study published today in the journal PLOS ONE, the team from the RIKEN Center for Life Science Technologies shows that the mutation, a single nucleotide polymorphism (SNP) in a gene that protects cells from oxidative stress, is found four times more frequently in women than in men.

Lung cancer is the leading cause of cancer-related deaths in many industrialized countries. Most deaths are due to long-term exposure to cigarette smoke, but non-smokers account for 10 -- 15% of cases.

Dr. Toshihisa Ishikawa and his team analyzed the DNA of patients with primary lung cancer and found that non-smoking Japanese women with two copies of the SNP (-617A) in the NFR2 gene had a markedly higher incidence of adenocarcinoma of the lung, as compared with non-smoking, homozygous males.

Furthermore, they find that both male and female lung cancer patients homozygous for the same SNP in the NRF2 gene survive lung cancer much better.

Nuclear factor erythroid-derived 2 (NF-E2)-related factor (NRF2) controls cellular adaptation to oxidants and electrophiles by inducing antioxidation and detoxification genes, and protects normal cells from external toxic challenges and oxidative stress.

Their study also suggests that lung cancer patients harboring a SNP (-617A) allele in the NRF2 gene in combination with the wild-type allele of the MDM2 gene have better prognosis.

"This is the first report providing clinical evidence that homozygous alleles for the SNP (-617A), one of the intrinsic genetic polymorphisms in the NRF2 gene, are associated with the overall survival of lung cancer patients," explains Dr. Ishikawa.

"The study strongly suggests that the presence of homozygous alleles for this SNP is a good prognostic biomarker for the assessment of the overall survival chances of patients with adenocarcinoma, as well as a practical tool for personalized cancer therapy," he concludes.

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Story Source:

The above story is based on materials provided by RIKEN.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

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Journal Reference:

1. Yasuko Okano, Uru Nezu, Yasuaki Enokida, Ming Ta Michael Lee, Hiroko Kinoshita, Alexander Lezhava, Yoshihide Hayashizaki, Satoshi Morita, Masataka Taguri, Yasushi Ichikawa, Takeshi Kaneko, Yutaka Natsumeda, Tomoyuki Yokose, Haruhiko Nakayama, Yohei Miyagi, Toshihisa Ishikawa. SNP (–617C>A) in ARE-Like Loci of the NRF2 Gene: A New Biomarker for Prognosis of Lung Adenocarcinoma in Japanese Non-Smoking Women. PLoS ONE, 2013; 8 (9): e73794 DOI: 10.1371/journal.pone.0073794

Note: If no author is given, the source is cited instead.

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