T-box for obesity, cancer and arthritis: 3 refer to 1

The worldwide epidemic of obesity has reached record levels, and what was once a problem only of industrialized countries is now also affecting the developing world. Consequently, scientists are working with great commitment to identify the mechanisms underlying the disease in order to find new treatments. As research in the past decade has shown, obesity is first and foremost a brain disease. Researchers at the Institute of Diabetes and Obesity (IDO) of Helmholtz Zentrum München have recently taken a further step in this direction. The team, partners in the German Center for Diabetes Research, have now discovered a molecular switch that controls the function of satiety neurons and therefore body weight. Applying a broad range of techniques, the scientists were then able to show that a transcription factor called Tbx3 plays a pivotal role in maintaining energy and sugar metabolism. In preliminary experiments with human neurons, they were able to show that they are no longer able to carry out their function in the absence of Tbx3. Besides, humans with genetic defects in the Tbx3 gene have long been reported to suffer from obesity.

Drs. Carmelo Quarta and  Alexandre Fisette, co-authors of this research, explained the principles: “Whether we’re hungry or feel full is largely determined in the brain, specifically in the hypothalamus. Two groups of neurons in the hypothalamus control body weight and energy balance via various molecular messengers. Like yin and yang, they help strike a good balance. While neurons known as AgRP increase appetite, their counterparts, POMC neurons, produce a sensation of satiety. However, if the interplay between the two is disturbed, the result can be obesity or type 2 diabetes. In our recent study we discovered that Tbx3 plays a key role in this mechanism. Specifically, in the absence of Tbx3, the neurons responsible for producing a feeling of satiety are no longer able to synthesize the expected molecular messengers. Both in a preclinical model and in fruit flies, the absence of Tbx3 leads to a kind of identity crisis of satiety neurons, resulting in obesity; and the same signaling pathways also appear to be present in humans. That is why we hope that Tbx3 may come into consideration one day as a target for drug therapies”.

Breast cancer is the most common malignancy worldwide and it is estimated that one out of eight women will develop breast cancer in their life time. Unfortunately, in spite of the enormous efforts invested to treat breast cancer there has been limited success because many patients still diagnosed too late. One important strategy to fight breast cancer is to identify more effective diagnostic targets for this disease. Previous study suggested Tbx3 as a potential biomarker for early stages of breast cancer; knocking down Tbx2and Tbx3 was shown to reverse key features of the melanoma and breast cancer phenotype, suggesting that it might be a useful target in the development of novel anti-cancer drugs. That is why a team from the Departments of Oncology and Pathology of the European Gaza Hospital, Palestine, was interested to ascertain if Tbx3 could be used as a specific marker for breast carcinoma. The study analyzed 51 breast cancer patient samples, that were collected by mastectomy. Scientists found that there are no significant correlations between Tbx3 protein level and several clinic-pathological parameters like include age, anatomic stage, cancer type, histological grade, tumor size, lymph node size, lymph node metastasis and tumor metastasis.

Similarly, no significant correlation between Tbx3 level and estrogen receptor (ER-alpha), progesterone receptor (PR-a), EGF receptor (HER2) and CA15-3 levels was found. Additionally, while the previous study showed that Tbx3 is mainly cytoplasmic in breast cancer cells only, data showed that Tbx3 is mainly cytoplasmic protein in both normal and breast cancer tissues. Significantly, the current study provides more statistical analysis to show the importance of Tbx3 as a marker of breast cancer cells. But that’s not the whole tale. Tbx3 could have a further importance in rheumatology, specifically for rheumatoid arthritis (RA). RA is characterized by chronic inflammation and primarily affects the synovial joints leading to tissue damage and physical disability. Furthermore, the consequences of immunological abnormalities and systemic inflammation may lead to premature mortality. Despite the introduction of new, effective therapies, not all patients respond to the available treatments. Therefore, there is an unmet need for novel drugs and better biomarkers that can improve early detection, determine prognosis and disease activity and stratify patients for various therapeutic options.

A team from the Department of Drug Design and Pharmacology, University of Copenhagen, demonstrated variations in the regulatory part of the Tbx3 gene, which may affect the observed difference in expression level of Tbx3 in spleen B lymphocytes, in addition to the increased in vitro B cell activation and proliferation upon stimulation through cell-bound IgM. Functional experiments showed that Tbx3 activity is inversely related to B cell activation in the mouse RA model (CIA). This suggests that TBX3 is a player in RA pathogenesis, by modulating B lymphocyte proliferation, but that it does not affect the development of B lymphocytes. In line with these reports of an anti-proliferative role for TBX3, lack of, or low expression of Tbx3, may enhance activation of B lymphocytes, manifested by proliferation and increased autoantibody production, which subsequently would cause severe arthritis in the CIA model. Furthermore, further preliminary data from the team, showed that TBX3 is a putative RA biomarker and that an increase in TBX3 serum levels in untreated arthritis reflects dysregulation of currently unidentified disease pathways.

Classic word is “one shot, two birds”; would Tbx lead to 3 ?

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Aliwaini S et al., Mol Clin Oncol. 2019 Jan; 10(1):105-112. 

Sardar S et al. Arthritis Res Ther. 2019 Jan 10; 21(1):16.

Clemmensen C et al. Nat Commun. 2018 Nov 20; 9(1):4975. 

Ruiz de Azua I et al. J Clin Invest. 2017; 127(11):4148-4162.

Informazioni su Dott. Gianfrancesco Cormaci 1365 Articoli
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry specialty in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Detentore di un brevetto sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of a patent concerning the production of bakery gluten-free products, starting from regular wheat flour). - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica, salute e benessere sui siti web salutesicilia.com e medicomunicare.it