colorectal cancer (crc) is the third most prevalent type of cancer worldwide. it is also the second most common cause of cancer-associated mortality; it accounted for about 9.2% of all cancer deaths in 2018, most of which were due to resistance to therapy. The main treatment for crc is surgery, generally associated with chemotherapy, radiation therapy and combination therapy. However, while chemo-radiotherapy kills differentiated cancer cells, mesenchymal stem-like cells are resistant to this treatment, and this can give rise to therapy-resistant tumors. our previous study isolated T88 primary colon cancer cells from a patient with sporadic colon cancer. These cells exhibited mesenchymal and epithelial features, high levels of epithelial-to-mesenchymal transition transcription factors, and stemness markers. in addition, it was revealed that lithium chloride (LiCl), a specific glycogen synthase kinase (GSK)-3β inhibitor, induced both the mesenchymal-to-epithelial transition and differentiation, and also reduced cell migration, stemness features and cell plasticity in these primary colon cancer cells. The aim of the present study was to investigate the effect of licl treatment on the viability of primary colon cancer cells exposed to 7 Gy delivered by high-energy photon beams, which corresponds to 6 megavolts of energy. To achieve this aim, the viability of irradiated T88 cells was compared with that of irradiated T88 cells pre-treated with licl. as expected, it was observed that licl sensitized primary colon cancer cells to high-energy photon irradiation treatment. notably, the decrease in cell viability was greater with combined therapy than with irradiation alone. To explore the molecular basis of this response, the effect of licl on the expression of Bax, p53 and Survivin, which are proteins involved in the apoptotic mechanism and in death escape, was analyzed. The present study revealed that licl upregulated the expression of pro-apoptotic proteins and downregulated the expression of proteins involved in survival. These effects were enhanced by high-energy photon irradiation, suggesting that licl could be used to sensitize colon cancer cells to radiation therapy.

Homeodomain-interacting protein kinase 2 (HIPK2) is a serine-threonine kinase that phosphorylates various transcriptional and chromatin regulators, thus modulating numerous important cellular processes, such as proliferation, apoptosis, DNA damage response, and oxidative stress. The role of HIPK2 in the pathogenesis of cancer and fibrosis is well established, and evidence of its involvement in the homeostasis of multiple organs has been recently emerging. We have previously demonstrated that Hipk2-null (Hipk2-KO) mice present cerebellar alterations associated with psychomotor abnormalities and that the double ablation of HIPK2 and its interactor HMGA1 causes perinatal death due to respiratory failure. To identify other alterations caused by the loss of HIPK2, we performed a systematic morphological analysis of Hipk2-KO mice. Post-mortem examinations and histological analysis revealed that Hipk2 ablation causes neuronal loss, neuronal morphological alterations, and satellitosis throughout the whole central nervous system (CNS); a myopathic phenotype characterized by variable fiber size, mitochondrial proliferation, sarcoplasmic inclusions, morphological alterations at neuromuscular junctions; and a cardiac phenotype characterized by fibrosis and cardiomyocyte hypertrophy. These data demonstrate the importance of HIPK2 in the physiology of skeletal and cardiac muscles and of different parts of the CNS, thus suggesting its potential relevance for different new aspects of human pathology.

The serine–threonine kinase homeodomain-interacting protein kinase 2 (HIPK2) modulates important cellular functions during development, acting as a signal integrator of a wide variety of stress signals, and as a regulator of transcription factors and cofactors. We have previously demonstrated that HIPK2 binds and phosphorylates High-Mobility Group A1 (HMGA1), an architectural chromatinic protein ubiquitously expressed in embryonic tissues, decreasing its binding affinity to DNA. To better define the functional role of HIPK2 and HMGA1 interaction in vivo, we generated mice in which both genes are disrupted. About 50% of these Hmga1/Hipk2 double knock-out (DKO) mice die within 12 h of life (P1) for respiratory failure. The DKO mice present an altered lung morphology, likely owing to a drastic reduction in the expression of surfactant proteins, that are required for lung development. Consistently, we report that both HMGA1 and HIPK2 proteins positively regulate the transcriptional activity of the genes encoding the surfactant proteins. Moreover, these mice display an altered expression of thyroid differentiation markers, reasonably because of a drastic reduction in the expression of the thyroid-specific transcription factors PAX8 and FOXE1, which we demonstrate here to be positively regulated by HMGA1 and HIPK2. Therefore, these data indicate a critical role of HIPK2/HMGA1 cooperation in lung and thyroid development and function, suggesting the potential involvement of their impairment in the pathogenesis of human lung and thyroid diseases.

Incontinentia pigmenti (IP; OMIM#308300) is a rare genetic disease resulting in neuroectodermal defects, which can lead to disability. At present, there is neither definitive cure available nor are there any sufficiently reliable insights to predict the severity of the disease. We launched the Incontinentia Pigmenti Genetic Biobank (IPGB) project (http://www.igb.cnr.it/ipgb) in 2015 to establish a large-scale deposit of biological samples, to provide detailed clinical information about children diagnosed with IP and to facilitate research. We have built a cohort comprising samples of 381 clinically confirmed patients with IP and 633 healthy individuals recruited through IP patients' associations. The collection includes 269 trios, 83 duos, and 95 families with at least two affected members and represents an extensive dataset (200 cooperative medical institutes, 139 in Italy and 61 worldwide) that enables a comprehensive phenotyping. Joining the IPGB guarantees all participants access to the results including the genetic testing of IP and the long-term storage of the samples. The IPGB is the largest IP sample collection and one of the largest rare-disease-oriented collections in the world and will be open to requests for access to data by the national and international scientific community.

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