p27, a cyclin-dependent kinase inhibitor, functions as a tumour suppressor in the nucleus but may acquire oncogenic properties when mislocalized to the cytoplasm. While KRAS mutations can induce p27 phosphorylation and cytoplasmic retention, the regulation and significance of p27 expression in wild-type (WT) KRAS colorectal cancer (CRC) remain unclear. This study investigated the relationship between WT KRAS status and p27 localization, as well as the potential roles of miR-221/222 expression and the CDKN1B V109G polymorphism in CRC susceptibility. Immunohistochemical analysis of 50 WT KRAS CRCs and adjacent normal tissues revealed the highest percentage of p27-positive cells in the superficial layer of normal mucosa and significantly fewer in the tumour center. WT KRAS tumours with KRAS expression showed increased p27 expression and predominant cytoplasmic localization at the invasive front, suggesting altered p27 subcellular distribution. miR-221/222 expression showed no correlation with p27 levels, and the CDKN1B V109G polymorphism was not associated with CRC risk. This study is the first to examine p27 localization in WT KRAS CRC. The observed association between WT KRAS expression and cytoplasmic p27 localization highlights a potential mechanism contributing to tumour progression through altered p27 function.

Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality. Microsatellite instability-high (MSI-H) tumors, resulting from defective DNA mismatch repair (MMR), represent a well-defined subtype with distinctive biological behavior and immunogenicity. In contrast, tumors with elevated microsatellite alterations at tetranucleotide repeats (EMAST) are less well characterized. EMAST can manifest with MSI or arise as an isolated form of instability, delineating discrete phenotypes underpinned by distinct mechanisms. This study aimed to characterize MSI and EMAST status in CRCs. By integrating instability profiles with clinicopathological features and mutational profiles of key driver genes, we aimed to refine molecular classification and advance understanding of CRC tumorigenesis. A total of 332 CRCs were analyzed for MSI and EMAST using established panels. Clinicopathological characteristics were recorded, and mutational profiling of KRAS, BRAF, CTNNB1, PIK3CA, and TP53 was performed. MLH1 expression was assessed using immunohistochemistry. MSS/EMAST-S tumors displayed profiles typical of chromosomally stable CRC, dominated by KRAS and followed by TP53 and PIK3CA mutations. MSI-H/EMAST-H tumors were characterized by frequent BRAF mutations, right-sided location, female predominance, and lower TP53 mutation rate, consistent with the classical hypermutated, immunogenic subtype. In contrast, MSS/EMAST-H tumors exhibited unique features, including enrichment for PIK3CA and CTNNB1 mutations, larger tumor size, and poorer differentiation, suggesting an intermediate phenotype between MSS and MSI-H. MSS/EMAST-L tumors aligned with chromosomally stable, KRAS/Wnt-driven CRC. In conclusion, MSS/EMAST-H tumors represent an underrecognized CRC subtype with intermediate genomic instability and a distinctive molecular profile, with potential implications for prognostic assessment and personalized therapeutic strategies.

Pancreatic neuroendocrine neoplasms (pNENs) are rare and heterogeneous tumors arising from neuroendocrine cells, representing approximately 10 % of all Gastro-Entero-Pancreatic neuroendocrine neoplasms. While most pNENs are sporadic, a subset is associated with genetic syndromes such as multiple endocrine neoplasia type 1 (MEN1) or von Hippel-Lindau disease (VHL). pNENs are further classified into functioning and non-functioning tumors, with distinct clinical behaviors, prognoses, and treatment approaches. This review explores genetic and environmental biomarkers that influence the risk, prognosis, and therapeutic responses in pNENs. The epidemiology of pNENs reveals an increasing incidence, primarily due to advancements in imaging techniques. Genetic factors play a pivotal role, with germline mutations in MEN1, VHL, and other genes contributing to familial pNENs. Somatic mutations, including alterations in the mTOR pathway and DNA maintenance genes such as DAXX and ATRX, are critical in sporadic pNENs. These mutations, along with epigenetic dysregulation and transcriptomic alterations, underpin the diverse clinical and molecular phenotypes of pNENs. Emerging evidence suggests that epigenetic changes, including DNA methylation profiles, can stratify pNEN subtypes and predict disease progression. Environmental and lifestyle factors, such as diabetes, smoking, and chronic pancreatitis, have been linked to an increased risk of sporadic pNENs. While the association between these factors and tumor progression is still under investigation, their potential role in influencing therapeutic outcomes warrants further study. Advances in systemic therapies, including somatostatin analogs, mTOR inhibitors, and tyrosine kinase inhibitors, have improved disease management. Biomarkers such as Ki-67, somatostatin receptor expression, and O6-methylguanine-DNA methyltransferase (MGMT) status are being evaluated for their predictive value. Novel approaches, including the use of circulating biomarkers (NETest, circulating tumor cells, and ctDNA) and polygenic risk scores, offer promising avenues for non-invasive diagnosis and monitoring. Despite these advancements, challenges remain, including the need for large, well-annotated datasets and validated biomarkers. Future research should integrate multi-omics approaches and leverage liquid biopsy technologies to refine diagnostic, prognostic, and therapeutic strategies. Interdisciplinary collaborations and global consortia are crucial for overcoming current limitations and translating research findings into clinical practice. These insights hold promise for improving prevention, early detection, and tailored treatments, ultimately enhancing patient outcomes.

Microsatellite instability (MSI) has been recognized as an important factor in colorectal cancer (CRC). It arises due to deficient mismatch repair (MMR), mostly attributed to MLH1 and MSH2 loss of function leading to a global MMR defect affecting mononucleotide and longer microsatellite loci. Recently, microsatellite instability at tetranucleotide loci, independent of the global MMR defect context, has been suggested to represent a distinct entity with possibly different consequences for tumorigenesis. It arises as a result of an isolated MSH3 loss of function due to its translocation from the nucleus to the cytoplasm under the influence of interleukin-6 (IL-6). In this study the influence of MSH3 and IL-6 signaling pathway polymorphisms (MSH3 exon 1, MSH3+3133A/G, IL-6-174G/C, IL-6R+48892A/C, and gp130+148G/C) on the occurrence of different types of microsatellite instability in sporadic CRC was examined by PCR–RFLP and real-time PCR SNP analyses. A significant difference in distribution of gp130+148G/C genotypes (p = 0.037) and alleles (p = 0.031) was observed in CRC patients with the C allele being less common in tumors with di- and tetranucleotide instability (isolated MSH3 loss of function) compared to tumors without microsatellite instability. A functional polymorphism in gp130 might modulate the IL-6 signaling pathway, directing it toward the occurrence of microsatellite instability corresponding to the IL-6-mediated MSH3 loss of function.

MicroRNAs (miRNAs) are critical post-transcriptional gene regulators and their involvement in sporadic colon cancer (CRC) tumorigenesis has been confirmed. In this study we investigated differences in miRNA expression in microsatellite stable (MSS/EMAST-S), microsatellite unstable marked by high elevated microsatellite alterations at selected tetranucleotide repeats (MSS/EMAST-H), and high microsatellite unstable (MSI-H/EMAST-H) tumor subgroups as well as in tumors with different clinicopathologic characteristics. An RT-qPCR analysis of miRNA expression was carried out on 45 colon cancer and adjacent normal tissue samples (15 of each group). Overall, we found three differentially expressed miRNAs between the subgroups. miR-92a-3p and miR-224-5p were significantly downregulated in MSI-H/EMAST-H tumors in comparison to other subgroups. miR-518c-3p was significantly upregulated in MSS/EMAST-H tumors in comparison to stable and highly unstable tumors. Furthermore, we showed that miR-143-3p and miR-145-5p were downregulated in tumors in comparison to normal tissues in all subgroups. In addition, we showed overexpression of miR-125b-5p in well-differentiated tumors and miR-451a in less advanced tumors. This is the first report on differences in miRNA expression profiles between MSS/EMAST-S, MSS/EMAST-H, and MSI-H/EMAST-H colorectal cancers. Our findings indicate that the miRNA expression signatures differ in CRC subgroups based on their instability status.

Microsatellite instability (MSI) represents an accumulation of frameshifts in short tandem repeats, microsatellites, across the genome due to defective DNA mismatch repair (dMMR). MSI has been associated with distinct clinical, histological, and molecular features of tumors and has proven its prognostic and therapeutic value in different types of cancer. Recently, another type of microsatellite instability named elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) has been reported across many different tumors. EMAST tumors have been associated with chronic inflammation, higher tumor stage, and poor prognosis. Nevertheless, the clinical significance of EMAST and its relation to MSI remains unclear. It has been proposed that EMAST arises as a result of isolated MSH3 dysfunction or as a secondary event in MSI tumors. Even though previous studies have associated EMAST with MSI-low phenotype in tumors, recent studies show a certain degree of overlap between EMAST and MSI-high tumors. However, even in stable tumors, (MSS) frameshifts in microsatellites can be detected as a purely stochastic event, raising the question of whether EMAST truly represents a distinct type of microsatellite instability. Moreover, a significant fraction of patients with MSI tumors do not respond to immunotherapy and it can be speculated that in these tumors, EMAST might act as a modifying factor.

Objectives: Pancreatic neuroendocrine tumors (NETs) are rare and account for about 7% of all cancers occurring in the pancreas. The epidermal growth factor family of receptors and their ligands play an important role in the growth and progression of tumors but their role in PNET development remains unknown. We hypothesized that functional single nucleotide polymorphisms (SNPs) in the EGF, EGFR, and HER2 genes might affect individual susceptibility to PNETs development and invasion like it was shown for various other tumors.Methods: We genotyped 68 patients with unresectable PNETs and 300 controls to evaluate the association between EGF, EGFR, and HER2 polymorphisms and susceptibility to PNETs and presence of metastases. Results: Genotype analysis of three SNPs EGF + 61A/G (rs4 4 4 4903), EGFR + 1562 G/A (rs11543848), and HER2 + 1963 A/G (rs1136201) showed that carriers of EGFR + 1562 AG genotype and AA/AG EGF + 61/HER2 + 1963 genotype combination are at risk of developing PNET. Furthermore, EGFR + 1562 AA genotype could be associated with the susceptibility to insulinoma development. Conclusions: Our results suggest involvement of EGFR signaling pathway in etiology of PNET develop-ment.(c) 2022 Published by Elsevier Inc.

Colorectal carcinoma (CRC) results from the accumulation of genetic mutations and alterations in signaling pathways. KRAS is mutated in 40% of CRC cases and is involved in increased tumor cells proliferation and survival. Although KRAS mutations are a dominant event in CRC tumorigenesis, increased wild-type KRAS expression has a similar effect on accelerated tumor growth. In this study, we investigated the KRAS status in correlation with clinicopathological features in sporadic CRC and more importantly the role of let-7a-5p and miR-544a-3p in the regulation of wild-type KRAS protein expression in the tumor center (T1) and invasive tumor front (T2). Analysis showed that 39.1% of tumor samples had KRAS mutations. In wild-type KRAS tumors, 62.0% were positive for KRAS protein expression and there was a higher percentage of KRAS-positive tumor cells and a higher intensity of immunohistochemical reaction in T2 than in T1 samples. This could not be attributed to differences in KRAS mRNA levels, suggesting regulation via miR-544a-3p expression which was significantly decreased in T2 samples. Furthermore, we demonstrated that tumor samples carrying the KRAS-LCS6 variant allele had significantly higher protein expression of the wild-type KRAS. Our results suggest the role of the KRAS-LCS6 polymorphism and miR-544a-3p expression in the regulation of wild-type KRAS protein expression in sporadic CRC.

Proinflammatory counterworks are important at different stages of tumor development, particularly during invasion and metastasis. Immune cells and their signal molecules can influence all stages of tumor progression, as well as therapeutic intervention. Proinflammatory cytokines are known triggers of growth in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). In this study, we explored the immunohistochemical expression of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), IL-2, and IL-6 in tissues from 43 GEP-NEN patients with tumors of gastric, duodenal, ileal, appendical, and colonic origin. The immunohistochemical expression of TNF-α was increased in tumor groups with high proliferation rates (Ki67; p = 0.034), as well as in those with higher tumor grades (p = 0.05). Moreover, the immunohistochemical expression of TNF-α positively correlated with death outcomes (p = 0.016). Expression of IL-6, IL-1β, and IL-2 displayed similar immunohistochemical expression patterns regardless of Ki67, although the expression between the ILs differed. Most GEP-NENs had high levels of IL-6 and lower levels of IL-1β and IL-2. Although further comprehensive studies are required for a complete understanding of activated mechanisms in proinflammatory protumoral microenvironment of GEP-NENs, TNF-α is a potential marker in the prognosis of those tumors.

Epidermal growth factor receptor (EGFR) expression is commonly upregulated in sporadic colorectal cancer (CRC) and its high expression is associated with poor prognosis in patients with CRC. CA-SSR1 is a dinucleotide CA repeat of the EGFR gene that can modulate EGFR transcription and is a potential target of the mismatch repair machinery in tumours with microsatellite instability (MSI). In the present study, 160 sporadic colon cancer samples were analysed for EGFR CA-SSR1 polymorphism and MSI status. Additionally, EGFR mRNA and protein expression levels in the tumour centre and in the invasive tumour front, compared with those in adjacent normal tissue samples, were evaluated in 80 tumour samples. An inverse association was identified between EGFR mRNA levels and the sum of repeats in both alleles of the CA-SSR1 polymorphism in normal tissues. Changes in CA-SSR1 were detected in the tumour centre as well as in the invasive tumour front and metastases in all MSI high (MSI-H) tumours. Analysis of EGFR expression at the mRNA and protein levels according to MSI status revealed lower EGFR mRNA and protein expression in MSI-H tumours than microsatellite-stable (MSS) tumours. Furthermore, higher EGFR levels in the invasive tumour front compared with in the tumour centre in MSS tumours were identified, suggesting a role of EGFR in tumour progression and higher invasive potential of MSS than MSI-H tumours.

Background/ Aim: Thrombin plays significant roles in various types of cancer. However, the expression levels of prothrombin, the thrombin precursor, in cancer remain unclear. Variants of the 3'end of the prothrombin gene lead to increased prothrombin expression. This study aimed to analyze prothrombin 3'end gene variants in colon tumor and adjacent normal tissue samples. Materials and Methods: The study group consisted of 93 patients suffering from colon adenocarcinoma. The 3'end of the prothrombin gene was analyzed by DNA sequencing. Results: Three variants, all previously associated with increased prothrombin expression were detected. Frequency of the FII 19911G allele was 46.77% and 47.85% in tumor and normal tissue, respectively. For the FII 20210A allele, the detected frequencies were 2.15% and 1.61%, respectively. The frequency of the FII c.1824T allele was 0.54% in both tissues. Four patients showed different genotypes in tumor and normal tissue. Conclusion: Prothrombin 3' end gene variants may play a role in colorectal cancer.

Juvenile spondyloarthritis (jSpA) is a complex disease with both genetic and environmental factors contributing to etiology. Multiple studies have shown that epigenetic mechanisms could link the environment and gene expression and thus provide a potential explanation for external contribution in the pathogenesis of numerous diseases, including rheumatic. Previously obtained gene signatures in jSpA patients revealed distinctive expression of important immune-related genes, though the mechanism(s) responsible for those alterations remained unknown. The purpose of this study was to evaluate the methylation levels of the TLR4, CXCR4, NLRP3, and PTPN12 gene promoter, along with the expression of several non-coding microRNAs (miR-150, miR-146a, miR-181a, and miR-223) in jSpA patients. Peripheral blood samples were obtained from 19 patients newly diagnosed with jSpA according to ILAR classification criteria for enthesitis-related arthritis (ErA) and seven gender- and age-matched subjects without any symptoms or signs of inflammatory disease. The expression of specific microRNAs was analyzed using qRT-PCR with predeveloped microRNA assays. DNA promoter region methylation status of selected genes was assessed by methylated DNA immunoprecipitation (MeDIP) analysis. Fold enrichment of immunoprecipitated DNA differed significantly for NLRP3 promoter site, while the expression analysis of selected microRNAs showed no significant difference in fold change between jSpA patients and healthy controls. The results indicated that epigenetic modifications in the initial phase of the disease could be responsible for some of the expression alterations in jSpA patients. Since NLRP3 has a crucial role in inflammasome assembly and inflammasomes have been shown to shape microbiota, it is tempting to assume that dysbiosis in jSpA patients can at least partially be explained by reduced NLRP3 expression due to hypermethylation, stressing for the first time the epigenetic contribution to jSpA pathophysiology.

BACKGROUND mutS homolog 2 (MSH2) deficiency may be involved in the development of microsatellite instability found in certain sporadic colorectal tumors. In addition to mutations or loss of heterozygosity resulting in complete loss of MSH2 function, polymorphisms affecting MSH2 expression have been also identified. Therefore, the aim of this study was to examine MSH2 status in sporadic colon cancer. MATERIALS AND METHODS MSH2 status was examined at the DNA, RNA and protein levels through loss of heterozygosity (LOH) analysis, quantitative real-time PCR and immunohistochemistry. MSH2 IVS10+12A>G polymorphism was examined by real-time single nucleotide polymorphism genotyping. RESULTS MSH2 LOH was more frequent in tumors larger than 5 cm (p=0.032), mRNA expression was also significantly lower and the same expression pattern was present in the corresponding normal mucosa of the same patient (p=0.013 and p=0.008, respectively). No association was found between IVS10+12A>G polymorphism and susceptibility to sporadic colon cancer. CONCLUSION Altered MSH2 expression detected in sporadic colon tumors pointing to its role in colorectal tumorigenesis without a hereditary component.

Background Juvenile spondyloarthritis (jSpA) is a diverse group of related syndromes with shared symptoms and pathogenic mechanisms in which both extrinsic environmental factors and intrinsic genetic background perpetuate inflammatory response through immune system alterations. Recently obtained gene signatures in jSpA patients revealed TLR4 and CXCR4 gene had increased, while NLRP3 and PTPN12 had decreased expression.1 Although gene expression is regulated by various mechanisms, the increasing numbers of studies is showing the importance of epigenetic mechanisms in this fundamental biological process. Objectives To investigate the possible mechanistic role of DNA promoter region methylation and several non-coding micro RNA (miR-150, miR-146a, miR-181a, miR-223) in jSpA patients regarding the expression of genes with previously observed alterations. Methods The expression of specific microRNAs was analysed in 8 jSpA patients and 5 matched controls using RT-PCR with predeveloped microRNA assays. Methylated DNA Immunoprecipitation (MeDIP) was performed in 19 patients and 7 controls. Enrichment in MeDIP fraction was determined by qRT-PCR using the AriaMx. Results The difference in fold enrichment of immunoprecipitated DNA was significant only for NLRP3 promotor site (p=0.0220). Expression analysis of selected miRs showed no significant difference in fold change between jSpA patients and healthy controls. Conclusions Our study indicated epigenetic modifications are probably responsible for some of the expression alterations in jSpA patients in the initial phase of the disease. Since NLRP3 has a crucial role in inflammasome assembly and inflammasomes have been shown to shape microbiota, it is reasonable to assume dysbiosis in jSpA patients can at least partially be explained by reduced NLRP3 expression due to hypermethylation, stressing for the first time the epigenetic contribution to jSpA pathophysiology. While it is still not clear if these epigenetic alterations are caused by genetic mutations in epigenetic factors or exposure to certain environmental factors that mediate the occurrence of aberrant epigenetic profiles, the disocvery of DNA methylation-based signature of the NLRP3 gene could have important implications in addressing extrinsic and intrinsic contribution to jSpA pathophysiology, whereas the possibility of reverting epigenetic modifications opens whole new prospects for therapeutic treatment of this complex disease. Reference [1] Lamot L, Borovecki F, Tambic Bukovac L, Vidovic M, Perica M, Gotovac K, et al. Aberrant expression of shared master-key genes contributes to the immunopathogenesis in patients with juvenile spondyloarthritis. PLoS ONE2014;9(12):e115416. Disclosure of Interest None declared

Cerebral palsy (CP) is a nonprogressive motor disorder caused by white matter damage in the developing brain. Recent epidemiological and clinical data suggest intrauterine infection/inflammation as the most common cause of preterm delivery and neonatal complications, including CP. Cyclooxygenases are key enzymes in the conversion of arachidonic acid to prostaglandins. The COX family consists of two isoforms, COX-1 and COX-2. In the brain, COX-2 is constitutively expressed at high levels on pyramidal neurons, while COX-1 is predominantly expressed by microglia and can be upregulated in pathological conditions, such as infection, ischemia and traumatic brain injury. Single nucleotide polymorphisms in the COX-1 and COX-2 gene could have profound effects on COX-1 and COX-2 expression and, directly or indirectly, influence the pathogenesis, development and severity of CP. In this study we investigated the association between single nucleotide polymorphisms of the COX-1 and COX-2 gene and susceptibility to cerebral palsy in very preterm infants. The results of our study showed the association between COX-1 high expression genotype (−842 AA) and COX-1 high expression allele −842A and risk of CP in infants with cystic periventricular leucomalacia (cPVL). Our results support an important role of COX-1 enzyme on microglial activation during neuroinflammation resulting in huge neuroinflammatory response and the proinflammatory mediator overproduction, with the serious white matter damage and CP development as a consequence.

Colorectal cancer (CRC) is one of the most common cancers and one of the leading causes of cancer death in the Western world.The disease arises from the accumulation of mutations in oncogenes, tumor suppressor genes and mismatch repair genes during progression from normal colon epithelium to adenoma and metastatic carcinoma.The majority of colorectal cancers arise in sporadic form.About one-third of patients with CRC have a family history of cancer and elevated risk for this malignant disease.However, only 5% of CRC arise from a germline mutation in high penetrant genes, adenomatous polyposis coli (APC) gene and DNA mismatch repair (MMR) genes.The most common hereditary CRC syndrome is Lynch syndrome defined by hereditary germline mutations in one the of MMR genes.The term hereditary non-polyposis colorectal cancer (HNPCC), previously used interchangeably with Lynch syndrome, now refers to a broader spectrum of familial CRC disorders that can mimic some clinical features of Lynch syndrome, but without germline mutations in MMR genes characteristic for Lynch syndrome.Distinguishing between the HNPCC disorders is important for clinicians, as the approach to surveillance for patients and their family members differs according to risk for CRC associated with each syndrome.This mini review will give some information about the most frequent molecular genetics changes in sporadic and hereditary colorectal cancer and its molecular stratification due to its heredity, somatic mutations and microsatellite instability.

CILJ: ranije provedeno ispitivanje genskoga izražaja bolesnika s juvenilnim spondiloartritisom (jSpA) pokazalo je promjene u izražaju cetiri gena (TLR4, NLRP3, CXCR4, PTPN12) ciji proteinski produkti sudjeluju u procesima važnima za razvoj bolesti. Kako bi se otkrili moguci epigenetski mehanizmi regulacije navedenih gena ispitana je metilacija njihovih promotora te izražaj mikroRNK za koje se provedenim istraživanjima utvrdilo da imaju ulogu u njihovom prepisivanju i obradi. METODE: DNA metilacija promotora ispitana je metodom metilirane DNA imunoprecipitacije (meDIP). Pretragom baza podataka odabrano je 4 mikroRNK (miR-150, miR-146a, miR-181a, miR-223) za koje se utvrdilo da bi mogle imati ulogu u regulaciji gena važnih za razvoj jSpA te je ispitan njihov izražaj pomocu RT-PCR metode s odgovarajucim Taqman mikroRNK probama. Sve analize provedene su u skupini od sedmero novootkrivenih, nelijecenih bolesnika s jSpA te u skupini od sedmero zdrave djece odgovarajuce dobi i spola. REZULTATI: statisticka analiza nije ukazala na znacajnu razliku u metilaciji promotorskih regija ispitivanih gena, no otkriven je trend pojacane metilacije gena PTPN12 u grupi bolesnika (p=0, 076). Nije bilo statisticke razlike u izražaju ispitivanih mikroRNA između bolesnika i skupine zdrave djece. ZAKLJUCAK: jSpA je kompleksna bolest u kojoj dolazi do poremecaja međudjelovanja imunoloskog sustava i cimbenika okolisa uz predisponirajuci genotip. Jedan od najvažnijih mehanizama kojima okolis utjece na procese unutar organizma je regulacija gena epigenetskim modifikacijama. U ovom istraživanju stoga je ispitan moguci utjecaj DNA metilacije i postranskripcijske modifikacije preko izabranih mikroRNK na gene koji su u bolesnika s jSpA pokazali razlike u izražaju. Rezultati nisu ukazali na statisticki znacajne razlike u metilaciji gena ili izražaju mikroRNK, sto bi moglo biti i zbog malog broja sudionika, no opažen je jasan trend pojacane metilacije gena PTPN12, cime se može objasniti smanjen izražaj toga gena u lijecenih i nelijecenih bolesnika s jSpA. Produkt navedenog gena prepoznat je kao glavni regulator migracije dendritickih stanica i imunoloskog odgovora ovisnog o T- limfocitima, negativni regulator upale i migracije stanica crijeva te pozitivni regulator aktivnosti osteoklasta, sto su sve procesi važni za razvoj jSpA. Rezultati naseg istraživanja u skladu su s rezultatima prijasnjih koji su pokazali kako se PTPN12 može utisati metilacijom. Nadalje, nedavno provedeno istraživanje pokazalo je da primjena hipometilacijskog agenta 5-Azac može pojacati izražaj PTPN12 gena u bolesnika s karcinomom dojke, cime se ukazalo i na moguci terapeutski potencijal ovog mehanizma. Stoga je primamljivo zakljuciti kako bi i nasi rezultati nakon potvrde u vecim skupinama bolesnika mogli poslužiti za razvoj novih metoda lijecenja bolesnika s jSpA.

Altered energy metabolism is a cancer hallmark as malignant cells tailor their metabolic pathways to meet their energy requirements. Glucose and glutamine are the major nutrients that fuel cellular metabolism, and the pathways utilizing these nutrients are often altered in cancer. Here, we show that the long ncRNA CCAT2, located at the 8q24 amplicon on cancer risk-associated rs6983267 SNP, regulates cancer metabolism in vitro and in vivo in an allele-specific manner by binding the Cleavage Factor I (CFIm) complex with distinct affinities for the two subunits (CFIm25 and CFIm68). The CCAT2 interaction with the CFIm complex fine-tunes the alternative splicing of Glutaminase (GLS) by selecting the poly(A) site in intron 14 of the precursor mRNA. These findings uncover a complex, allele-specific regulatory mechanism of cancer metabolism orchestrated by the two alleles of a long ncRNA.