Human Chromosome 11p15 Research Articles

PinX1 plays multifaceted roles in human cancers: a review and perspectives.

Pin2/TRF1 interacting protein X1 (PinX1), a telomerase inhibitor, is located at human chromosome 8p23. This region is important for telomere length maintenance and chromosome stability, both of which are essential for regulating human ageing and associated diseases. We investigated the research progress of PinX1 in human cancers. In cancers, the expression levels of PinX1 mRNA and protein vary according to cancer cell types, and PinX1 plays a critical role in the regulation of cancer development and progression. Additionally, a review of the literature indicates that PinX1 is involved in mitosis and affects the sensitivity of cancer cells to radiation-induced DNA damage. Therefore, PinX1 has therapeutic potential for cancer, and understanding the function of PinX1 in the regulation of cancers is crucial for improving treatment. In this review, we discuss the expression level of PinX1 in a variety of cancers and how it affects the implicated pathways. Additionally, we outline the function of PinX1 in cancer cells and provide a theoretical basis for PinX1-related cancer therapy. PinX1 has promising prospects in future cancer therapeutics. This review may provide theoretical support for researchers in this field.

Fgf17: A regulator of the mid/hind brain boundary in mammals

The Fibroblast growth factor (FGFs) family consists of at least 22 members that exert their function by binding and activating fibroblast growth factor receptors (FGFRs). The Fgf8/FgfD subfamily member, Fgf17, is located on human chromosome 8p21.3 and mouse chromosome 14 D2. In humans, FGF17 can be alternatively spliced to produce two isoforms (FGF17a and b) whereas three isoforms are present in mice (Fgf17a, b, and c), however, only Fgf17a and Fgf17b produce functional proteins. Fgf17 is a secreted protein with a cleavable N-terminal signal peptide and contains two binding domains, namely a conserved core region and a heparin binding site. Fgf17 mRNA is expressed in a wide range of different tissues during development, including the rostral patterning centre, midbrain-hindbrain boundary, tailbud mesoderm, olfactory placode, mammary glands, and smooth muscle precursors of major arteries. Given its broad expression pattern during development, it is surprising that adult Fgf17−/− mice displayed a rather mild phenotype; such that mutants only exhibited morphological changes in the frontal cortex and mid/hind brain boundary and changes in certain social behaviours. In humans, FGF17 mutations are implicated in several diseases, including Congenital Hypogonadotropic Hypogonadism and Kallmann Syndrome. FGF17 mutations contribute to CHH/KS in 1.1% of affected individuals, often presenting in conjunction with mutations in other FGF pathway genes like FGFR1 and FLRT3. FGF17 mutations were also identified in patients diagnosed with Dandy-Walker malformation and Pituitary Stalk Interruption Syndrome, however, it remains unclear how FGF17 is implicated in these diseases. Altered FGF17 expression has been observed in several cancers, including prostate cancer, hematopoietic cancers (acute myeloid leukemia and acute lymphoblastic leukemia), glioblastomas, perineural invasion in cervical cancer, and renal cell carcinomas. Furthermore, FGF17 has demonstrated neuroprotective effects, particularly during ischemic stroke, and has been shown to improve cognitive function in ageing mice.

A Number of the N-terminal RASSF Family: RASSF7.

The Ras association domain family 7 (RASSF7, also named HRC1), a potential tumor-related gene, located on human chromosome 11p15, has been identified as an important member of the N-terminal RASSF family. Whereas, the molecular biological mechanisms of RASSF7 in tumorigenesis remain to be further established. We perform a systematic review of the literature and assessment from PUBMED and MEDLINE databases in this article. RASSF7 plays a significant role in mitosis, microtubule growth, apoptosis, proliferation and differentiation. Many research literature shows that the RASSF7 could promote the occurrence and advance of human tumors by regulating Aurora B, MKK4, MKK7, JNK, YAP, MEK, and ERK, whereas, it might inhibit c-Myc and thus lead to the suppression of tumorigenesis. The pregulation of RASSF7 often occurs in various malignancies such as lung cancer, neuroblastoma, thyroid neoplasm, hepatocellular cancer, breast cancer and gastric cancer. The expression stage of RASSF7 is positively correlated with the tumor TNM stage. In this review, we primarily elaborate on the acknowledged structure and progress in the various biomechanisms and research advances of RASSF7, especially the potential relevant signaling pathways. We hope that RASSF7 , a prospective therapeutic target for human malignancies, could play an available role in future anti-cancer treatment.

The lncRNA H19/miR-29a-3p/SNIP1/c-myc regulatory axis is involved in pulmonary fibrosis induced by Nd2O3.

Some rare earth elements are occupational and environmental toxicants and can cause organ and systemic damage; therefore, they have attracted global attention. Neodymium oxide (Nd2O3) is a rare earth element that is refined and significantly utilized in China. The long noncoding RNA (lncRNA) H19 is encoded by the H19/IGF2 imprinted gene cluster located on human chromosome 11p15.5. H19 has become a research focus due to its ectopic expression leading to the promotion of fibrosis. However, the mechanisms by which it causes pulmonary fibrosis are elusive. This investigation indicates that biologically active Nd2O3 increases H19, SNIP1, and c-myc, decreases miR-29a-3p, accelerates macrophage M2 polarization, and causes pulmonary fibrosis in mice lung tissues. In macrophage-differentiated THP-1 cells, Nd2O3 (25 μg/ml) enhanced H19, SNIP1, and c-myc, reduced miR-29a-3p, accelerated macrophages M2 polarization, and stimulated fibrogenic cytokine (TGF-β1) secretion. Furthermore, the coculturing of Nd2O3-treated macrophage-differentiated THP-1 cells. And human embryonic lung fibroblast cells activated lung fibroblast, which increases the levels of collagen I, α-SMA, p-Smad2/3, and Smad4, whereas H19 knockdown or miR-29a-3p upregulation in macrophages had opposite effects. Moreover, it was revealed that H19/miR-29a-3p/SNIP1/c-myc regulatory axis is involved in pulmonary fibrosis induced by Nd2O3. Therefore, this study provides new molecular insights into the mechanism of pulmonary fibrosis by Nd2O3.

Recurrent human 16p11.2 microdeletions in type I Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome patients in Chinese Han population.

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, a severe congenital malformation of the female genital tract, is a highly heterogeneous disease which has no clear etiology. Previous studies have suggested that copy number variations (CNVs) and single-gene mutations might contribute to the development of MRKH syndrome. In particular, deletions in 16p11.2, which are suggested to be involved in several congenital diseases, have been reported in Chinese type II MRKH patients and European MRKH patients. However, few CNVs including 16p11.2 microdeletions were identified in Chinese type I MRKH cases although it accounted for the majority of MRKH patients in China. Thus, we conducted a retrospective study to identify whether CNVs at human chromosome 16p11.2 are risk factors of type I MRKH syndrome in the Chinese Han population. We recruited 143 patients diagnosed with type I MRKH between 2012 and 2014. Five hundred unrelated Chinese without congenital malformation were enrolled in control group, consisting of 197 from the 1000 Genomes Project and 303 from Fudan University. Quantitative PCR, array comparative genomic hybridization, and sanger sequencing were conducted to screen and verify candidate variant. Our study identified recurrent 16p11.2 microdeletions of approximately 600 kb in two out of the 143 type I MRKH syndrome patients using high-density array-based comparative genomic hybridization (aCGH), while no 16p11.2 deletion was found in the control group. We did not find any mutations in TBX6 gene in our samples. The results of the study identify 16p11.2 deletion in Chinese MRKH I patients for the first time, as well as support the contention that 16p11.2 microdeletions are associated with MRKH syndrome in both types across populations. It is suggested that 16p11.2 microdeletions should be included in molecular diagnosis and genetic counseling of female reproductive tract disorders.

SUMO1-regulated DBC1 promotes p53-dependent stress-induced apoptosis of lens epithelial cells.

Deleted in breast cancer 1 (DBC1) was initially identified from a homozygously deleted region in human chromosome 8p21. It has been well established that DBC1 plays a dual role during cancer development. Depending on the physiological context, it can promote or inhibit tumorigenesis. Whether it plays a role in lens pathogenesis remains elusive. In the present study, we demonstrated that DBC1 is highly expressed in lens epithelial cells from different vertebrates and in retina pigment epithelial cells as well. Moreover, DBC1 is SUMOylated through SUMO1 conjugation at K591 residue in human and mouse lens epithelial cells. The SUMOylated DBC1 is localized in the nucleus and plays an essential role in promoting stress-induced apoptosis. Silence of DBC1 attenuates oxidative stress-induced apoptosis. In contrast, overexpression of DBC1 enhances oxidative stress-induced apoptosis, and this process depends on p53. Mechanistically, DBC1 interacts with p53 to regulate its phosphorylation status at multiple sites and the SUMOylation of DBC1 enhances its interaction with p53. Together, our results identify that DBC1 is an important regulator mediating stress-induced apoptosis in lens, and thus participates in control of lens cataractogenesis.

The Long Non-Coding RNA ANRIL in Cancers.

ANRIL (Antisense Noncoding RNA in the INK4 Locus), a long non-coding RNA encoded in the human chromosome 9p21 region, is a critical factor for regulating gene expression by interacting with multiple proteins and miRNAs. It has been found to play important roles in various cellular processes, including cell cycle control and proliferation. Dysregulation of ANRIL has been associated with several diseases like cancers and cardiovascular diseases, for instance. Understanding the oncogenic role of ANRIL and its potential as a diagnostic and prognostic biomarker in cancer is crucial. This review provides insights into the regulatory mechanisms and oncogenic significance of the 9p21 locus and ANRIL in cancer.

A variant in the LDL receptor-related protein encoding gene LRP4 underlying polydactyly and phalangeal synostosis in a family of Pakistani origin.

A family of Pakistani origin, segregating polydactyly, and phalangeal synostosis in an autosomal dominant manner, has been investigated and presented in the present report. Whole-exome sequencing (WES), followed by segregation analysis using Sanger sequencing, revealed a heterozygous missense variant [c.G1696A, p.(Gly566Ser)] in the LRP4 gene located on human chromosome 11p11.2. Homology protein modeling revealed the mutant Ser566 generated new interactions with at least four other amino acids and disrupted protein folding and function. Our findings demonstrated the first direct evidence of involvement of LRP4 in causing polydactyly and phalangeal synostosis in the same family. This study highlighted the importance of inclusion of LRP4 gene in screening individuals presenting polydactyly in hands and feet, and phalangeal synostosis in the same family.

Surfactant Metabolism Dysfunction Type 3 (SMDP3)

Surfactant (surface-active-agent) is a compound of phospholipids and proteins which are synthesized and secreted into the alveolus by type II epithelial cells, where it functions to decrease surface tension, maintaining alveolar expansion, to facilitate pulmonary compliance. Surfactant proteins (SP)A, B, C, D represent around 8% of total components, but has vital role in optimizing rapid adsorption and spreading of phospholipids. ATP-binding cassette sub-family A member 3, protein that encoded by ABCA3 gene, which located in human chromosome 16p13.3, is synthesized in endoplasmic reticulum and migrated to lysosomal-derived organelles of alveolar type II cells, formally known as lamellar bodies. Once accumulate into the membrane, ABCA3 can directed surfactant phospholipid into the lumen of lamellar bodies and create tight packed of surfactant lipids and proteins. Mutation of the ATP-binding cassette transporter gene ABCA3 cause failure in lamellar body synthesis and result in decreased production of surfactant, along with respiratory distress syndrome, and fatal respiratory failure.

Abstract 3318: Frequent loss of CACNA1C, a calcium voltage-gated channel subunit is associated with lung adenocarcinoma progression and poor prognosis

Abstract Lung adenocarcinoma (LUAD) is a common non-small cell lung cancer disease most commonly found among non-smokers. This cancer is usually diagnosed at an advanced stage and can recur frequently and quickly with low chances of survival. Moreover, LUAD patients live with the fear of developing second primary tumors in their lifetime. A high-resolution SNP array (Affymetrix 250 NspI) analysis of primary LUAD tumors and their follow-up mucosal biopsies identified frequent copy neutral loss of heterozygosity (LOH, loss of 59 SNPs) of CACNA1C, a calcium voltage-gated channel subunit, located to human chromosome 12p13.33. Transcriptomic profiling utilizing The Cancer Genome Atlas (TCGA) revealed frequent loss of mRNA expression of CACNA1C in LUAD tumors (n=515) compared to the normal counterparts (n=59). Loss of CACNA1C mRNA expression was significantly associated with stage, grade, lymph node metastasis, P53 gene mutation, and worst survival of the LUAD patients. Epigenetic alteration such as DNA methylation could be a potential mechanism of the inactivation of a tumor suppressor gene (TSG) other than LOH, frequently observed in human cancers. We also recorded significantly higher promoter methylation of CACNA1C in the above LUAD tumors compared to the normal counterparts. Higher promoter methylation of CACNA1C was significantly associated with stage, grade, lymph node metastasis, P53 gene mutation, and poor survival of the LUAD patients. Thus, both allelic loss and methylation appear to be potential mechanisms behind the loss of function of CACNA1C in LUAD patients. Further validation of CACNA1C expression at the protein level confirmed its high membranous expression in normal lung tissues. Analysis of an independent cohort of LUAD subjects revealed significant loss of CACNA1C in primary tumors (n=30) and lymph node metastases (n=10) of LUAD patients compared to their normal counterparts. Loss of CACNA1C protein expression was associated with lymph node metastasis and stage-wise progression of the LUAD patients. Further validation of CACNA1C expression in larger cohorts and functional characterization would be beneficial for potential biomarkers and therapeutic development in the longer run. On the other hand, epigenetically silenced TSGs can be reactivated by CRISPR-CAS9-based technology or demethylating agents, implicating the therapeutic promise of targeting TSGs. Citation Format: Saanvi Dasgupta, Srijan Acharya, Mohammad A. Khan, Paramahansa Pramanik, Stephen M. Marbut, Furhan Yunus, Jose N. Galeas, Seema Singh, Ajay P. Singh, Santanu Dasgupta. Frequent loss of CACNA1C, a calcium voltage-gated channel subunit is associated with lung adenocarcinoma progression and poor prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3318.

A novel lncRNA-mediated epigenetic regulatory mechanism in periodontitis.

Periodontitis is a highly prevalent chronic inflammatory disease with an exaggerated host immune response, resulting in periodontal tissue destruction and potential tooth loss. The long non-coding RNA, LncR-ANRIL, located on human chromosome 9p21, is recognized as a genetic risk factor for various conditions, including atherosclerosis, periodontitis, diabetes, and cancer. LncR-APDC is an ortholog of ANRIL located on mouse genome chr4. This study aims to comprehend the regulatory role of lncR-APDC in periodontitis progression. Our experimental findings, obtained from lncR-APDC gene knockout (KO) mice with induced experimental periodontitis (EP), revealed exacerbated bone loss and disrupted pro-inflammatory cytokine regulation. Downregulation of osteogenic differentiation occurred in bone marrow stem cells harvested from lncR-APDC-KO mice. Furthermore, single-cell RNA sequencing of periodontitis gingival tissue revealed alterations in the proportion and function of immune cells, including T and B cells, macrophages, and neutrophils, due to lncR-APDC silencing. Our findings also unveiled a previously unidentified epithelial cell subset that is distinctively presenting in the lncR-APDC-KO group. This epithelial subset, characterized by the positive expression of Krt8 and Krt18, engages in interactions with immune cells through a variety of ligand-receptor pairs. The expression of Tff2, now recognized for its role in chronic inflammatory conditions, exhibited a notable increase across various tissue and cell types in lncR-APDC deficient mice. Additionally, our investigation revealed the potential for a direct binding interaction between lncR-APDC and Tff2. Intra-gingival administration of AAV9-lncR-APDC was shown to have therapeutic effects in the EP model. In conclusion, our results suggest that lncR-APDC plays a critical role in the progression of periodontal disease and holds therapeutic potential for periodontitis. Furthermore, the presence of the distinctive epithelial subpopulation and significantly elevated Tff2 levels in the lncR-APDC-silenced EP model offer new perspectives on the epigenetic regulation of periodontitis pathogenesis.

Integrated bioinformatics analysis for the identification of hub genes and signaling pathways related to circANRIL.

BackgroundAntisense noncoding RNA in the INK4 locus (ANRIL) is located on human chromosome 9p21, and modulation of ANRIL expression mediates susceptibility to some important human disease, including atherosclerosis (AS) and tumors, by affecting the cell cycle circANRIL and linear ANRIL are isoforms of ANRIL. However, it remains unclear whether these isoforms have distinct functions. In our research, we constructed a circANRIL overexpression plasmid, transfected it into HEK-293T cell line, and explored potential core genes and signaling pathways related to the important differential mechanisms between the circANRIL-overexpressing cell line and control cells through bioinformatics analysis.MethodsStable circANRIL-overexpressing (circANRIL-OE) HEK-293T cells and control cells were generated by infection with the circANRIL-OE lentiviral vector or a negative control vector, and successful transfection was confirmed by conventional flurescence microscopy and quantitative real-time PCR (qRT-PCR). Next, differentially expressed genes (DEGs) between circANRIL-OE cells and control cells were detected. Subsequently, Gene Ontology (GO) biological process (BP) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to explore the principal functions of the significant DEGs. A protein–protein interaction (PPI) network and competing endogenous RNA (ceRNA) network were constructed in Cytoscape to determine circularRNA (circRNA)- microRNA(miRNA)-messenger RNA (mRNA) interactions and hub genes, and qRT-PCR was used to verify changes in the expression of these identified target genes.ResultsThe successful construction of circANRIL-OE cells was confirmed by plasmid sequencing, visualization with fluorescence microscopy and qRT-PCR. A total of 1745 DEGs between the circANRIL-OE group and control were identified, GO BP analysis showed that these genes were mostly related to RNA biosynthesis and processing, regulation of transcription and signal transduction. The KEGG pathway analysis showed that the up regulated DEGs were mainly enriched in the MAPK signaling pathway. Five associated target genes were identified in the ceRNA network and biological function analyses. The mRNA levels of these five genes and ANRIL were detected by qRT-PCR, but only COL5A2 and WDR3 showed significantly different expression in circANRIL-OE cells.

BRCA1-Associated Protein 1 (BAP-1) as a Prognostic and Predictive Biomarker in Clear Cell Renal Cell Carcinoma: A Systematic Review

BACKGROUND: The gene that encodes BRCA1-associated protein 1 (BAP1) has been reported to be dysregulated in several human cancers such as uveal melanoma, malignant pleural mesothelioma, hepatocellular carcinoma, thymic epithelial tumors, and clear-cell renal cell carcinoma (ccRCC). The gene is located on the human chromosome 3p21.3, encoding a deubiquitinase and acts as a classic two-hit tumor suppressor gene. BAP1 predominantly resides in the nucleus, where it interacts with several chromatin-associated factors, as well as regulates calcium signaling in the cytoplasm. As newer therapies continue to evolve for the management of RCC, it is important to understand the role of BAP1 mutation as a prognostic and predictive biomarker. OBJECTIVE: We aimed to systematically evaluate the role of BAP1 mutations in patients with RCC in terms of its impact on prognosis and its role as a predictive biomarker. METHODS: Following PRISMA guidelines, we performed a systematic literature search using PubMed and Embase through March 2021. Titles and abstracts were screened to identify articles for full-text and then a descriptive review was performed. RESULTS: A total of 490 articles were initially identified. Ultimately 71 articles that met our inclusion criteria published between 2012–2021 were included in the analysis. Data were extracted and organized to reflect the role of BAP1 alterations as a marker of prognosis as well as a marker of response to treatments, such as mTOR inhibitors, VEGF tyrosine kinase inhibitors, and immune checkpoint inhibitors. CONCLUSIONS: Alterations in BAP1 appear to be uniformly associated with poor prognosis in patients with RCC. Knowledge gaps remain with regard to the predictive relevance of BAP1 alterations, especially in the context of immunotherapy. Prospective studies are required to more precisely ascertain the predictive value of BAP1 alterations in RCC.

Rrn3 gene knockout affects ethanol-induced locomotion in adult heterozygous zebrafish.

Genome-wide analysis has identified the transcription factor, RRN3 (or TIF-1A), on human chromosome 16p13.11 as a candidate gene associated with mental disorders. Both genetic and biochemical experiments have demonstrated that RRN3 plays a major role in the transcriptional regulation of ribosomal DNA and cell growth. Previous research has suggested that loss of RRN3 from mature neurons reproduces the chronic nature of neurodegenerative processes. Here, we report the first generation and characterization of rrn3 mutant zebrafish in larval and adult stages using the CRISPR/Cas9 genome editing technique. Homozygous knockout zebrafish exhibited morphological changes, such as pericardial oedema and deformed heads, and died at the larval stage of embryonic development. Behaviourally, the locomotion and shoaling behaviour of adult rrn3+/- zebrafish was not significantly different compared with rrn3+/+ zebrafish. Notably, rrn3+/- zebrafish demonstrated abnormal locomotor activity in response to ethanol. We found decreased norepinephrine expression in the brains of rrn3+/- zebrafish when treated with ethanol. In summary, our results indicated that rrn3 was closely associated with early embryonic development in zebrafish. Furthermore, behavioural and neurochemical research revealed the importance of genetic differences in drug sensitivity. The results suggest that caution should be taken when treating RRN3 heterozygous patients.

Development and Evaluation of a Droplet Digital PCR Assay for 8p23 β-Defensin Cluster Copy Number Determination.

IntroductionIt has been proposed that the copy number (CN) variation (CNV) in β-defensin genes (DEFB) on human chromosome 8p23 determines phenotypic differences in inflammatory diseases. However, no method for accurate and easy DEFB CN quantification is yet available.ObjectiveDroplet digital polymerase chain reaction (ddPCR) is a novel method for CNV quantification and has been used for genes such as CCL4L, CCL3L1, AMY1, and HER2. However, to date, no ddPCR assay has been available for DEFB CN determination. In the present study, we aimed to develop and evaluate such a ddPCR assay.MethodsThe assay was designed using DEFB4 and RPP30 as the target and the reference gene, respectively. To evaluate the assay, 283 DNA samples with known CNs previously determined using the multiple ligation-dependent probe amplification (MLPA) method, the current gold standard, were used as standards. To discover the optimal DNA template amount, we tested 80 to 2.5 ng DNA by a serial of one to two dilutions of eight samples. To evaluate the reproducibility of the assay, 31 samples were repeated to calculate the intra- and inter-assay variations. To further validate the reliability of the assay, the CNs of all 283 samples were determined using ddPCR. To compare results with those using quantitative PCR (qPCR), DEFB CNs for 48 samples were determined using qPCR with the same primers and probes.ResultsIn a one-dimensional plot, the positive and negative droplets were clearly separated in both DEFB4 and RPP30 detection channels. In a two-dimensional plot, four populations of droplets were observed. The 20 ng template DNA proved optimal, with either high (80 ng) or low (10, 5, 2.5 ng) template input leading to ambiguous or inaccurate results. For the 31 standard samples, DEFB CNs were accurately determined with small intra- and inter-assay variations (coefficient of variation < 0.04 for both). In the validation cohort, ddPCR provided the correct CN for all 283 samples with high confidence. qPCR measurements for the 48 samples produced noisy data with high uncertainty and low accuracy.ConclusionsddPCR is an accurate, reproducible, easy-to-use, cheap, high-throughput method for DEFB CN determination. ddPCR could be applied to DEFB CN quantification in large-scale case–control studies.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40291-021-00546-2.

Human chromosome 3p21.3 carries TERT transcriptional regulators in pancreatic cancer

Frequent loss of heterozygosity (LOH) on the short arm of human chromosome 3 (3p) region has been found in pancreatic cancer (PC), which suggests the likely presence of tumor suppressor genes in this region. However, the functional significance of LOH in this region in the development of PC has not been clearly defined. The human telomerase reverse transcriptase gene (hTERT) contributes to unlimited proliferative and tumorigenicity of malignant tumors. We previously demonstrated that hTERT expression was suppressed by the introduction of human chromosome 3 in several cancer cell lines. To examine the functional role of putative TERT suppressor genes on chromosome 3 in PC, we introduced an intact human chromosome 3 into the human PK9 and murine LTPA PC cell lines using microcell-mediated chromosome transfer. PK9 microcell hybrids with an introduced human chromosome 3 showed significant morphological changes and rapid growth arrest. Intriguingly, microcell hybrid clones of LTPA cells with an introduced human chromosome 3 (LTPA#3) showed suppression of mTert transcription, cell proliferation, and invasion compared with LTPA#4 cells containing human chromosome 4 and parental LTPA cells. Additionally, the promoter activity of mTert was downregulated in LTPA#3. Furthermore, we confirmed that TERT regulatory gene(s) are present in the 3p21.3 region by transfer of truncated chromosomes at arbitrary regions. These results provide important information on the functional significance of the LOH at 3p for development and progression of PC.

Dominant role of CDKN2B/p15INK4B of 9p21.3 tumor suppressor hub in inhibition of cell-cycle and glycolysis

Human chromosome 9p21.3 is susceptible to inactivation in cell immortalization and diseases, such as cancer, coronary artery disease and type-2 diabetes. Although this locus encodes three cyclin-dependent kinase (CDK) inhibitors (p15INK4B, p14ARF and p16INK4A), our understanding of their functions and modes of action is limited to the latter two. Here, we show that in vitro p15INK4B is markedly stronger than p16INK4A in inhibiting pRb1 phosphorylation, E2F activity and cell-cycle progression. In mice, urothelial cells expressing oncogenic HRas and lacking p15INK4B, but not those expressing HRas and lacking p16INK4A, develop early-onset bladder tumors. The potency of CDKN2B/p15INK4B in tumor suppression relies on its strong binding via key N-terminal residues to and inhibition of CDK4/CDK6. p15INK4B also binds and inhibits enolase-1, a glycolytic enzyme upregulated in most cancer types. Our results highlight the dual inhibition of p15INK4B on cell proliferation, and unveil mechanisms whereby p15INK4B aberrations may underpin cancer and non-cancer conditions.

Sex-Specific Stress-Related Behavioral Phenotypes and Central Amygdala Dysfunction in a Mouse Model of 16p11.2 Microdeletion

BackgroundSubstantial evidence indicates that a microdeletion on human chromosome 16p11.2 is linked to neurodevelopmental disorders, including autism spectrum disorder (ASD). Carriers of this deletion show divergent symptoms besides the core features of autism spectrum disorder, such as anxiety and emotional symptoms. The neural mechanisms underlying these symptoms are poorly understood. MethodsWe used mice heterozygous for a deletion allele of the genomic region corresponding to the human 16p11.2 microdeletion locus (i.e., 16p11.2 del/+ mice) and their sex-matched wild-type littermates for the study and examined their anxiety-related behaviors, auditory perception, and central amygdala circuit function using behavioral, circuit tracing, and electrophysiological techniques. ResultsMice heterozygous for a deletion allele of the genomic region corresponding to the human 16p11.2 microdeletion locus (i.e., 16p11.2 del/+ mice) had sex-specific anxiety-related behavioral and neural circuit changes. Specifically, we found that female, but not male, 16p11.2 del/+ mice showed enhanced fear generalization—a hallmark of anxiety disorders—after auditory fear conditioning and displayed increased anxiety-like behaviors after physical restraint stress. Notably, such sex-specific behavioral changes were paralleled by an increase in activity in central amygdala neurons projecting to the globus pallidus in female, but not male, 16p11.2 del/+ mice. ConclusionsTogether, these results reveal female-specific anxiety phenotypes related to 16p11.2 microdeletion syndrome and a potential underlying neural circuit mechanism. Our study therefore identifies previously underappreciated sex-specific behavioral and neural changes in a genetic model of 16p11.2 microdeletion syndrome and highlights the importance of investigating female-specific aspects of this syndrome for targeted treatment strategies.

Inter-3' ends CpG islands are enriched in human chromosome 19p13.3 region

Metabolic disease is a pandemic in modern times. However, understanding of the genomic basis associated with metabolism remains to be further elucidated. CpG islands are the genomic regions enriched in cytosine nucleotide (C) and guanine nucleotide (G), mostly located at promoters and contain the 5' end of the gene transcript. In this study, we utilize the UCSC Genome Browser to map the genomic locations and extract the CpG island tracks that are associated with the genes encoding functions in cell metabolism or metabolic disease. We identified a new genomic signature, namely inter-3' end CpG island (ITCI), associated with the genes encoding major metabolic regulators or enzymes in the human chromosome 19p13.3 region. In this region, the gene encoding a major metabolic regulator, CREB3L3, possesses a conserved CpG island in its 3' end. This unique ITCI genomic signature has been found in nine pairs of genes in the human chromosome 19p13.3 region. Many of these genes are associated with metabolism. In conclusion, we discovered a new type of genomic signature, ITCI, which is featured by a dozen of metabolic genes possessing conserved CpG islands in their 3' ends, in a specific human chromosome. Identification of ITCI signature and decoding of the ITCI-associated associated metabolic genes provide important insights into the genomic basis of metabolism or metabolic disease.

Long noncoding RNA ANRIL as a novel biomarker in human cancer.

The long noncoding RNA ANRIL, located in the human chromosome 9p21 region, has been reported to be involved in tumor progression. ANRIL regulates gene expression via recruiting PRC2 or titrating miRNA; it also participates in signaling pathways. Evidence has indicated that ANRIL is overexpressed in many cancer types and is capable of enhancing cell proliferation and cell cycle progression and inhibiting apoptosis and senescence. ANRIL has the potential to serve as a biomarker for diagnosis and prognosis in cancer. In this article we focus on recent advances in studies of the oncogenic role of ANRIL and its potential role in cancer medicine.