In pediatric acute myeloid leukemia (AML), chromosomal abnormalities leading to a disruption of the lysine methyltransferase 2A (KMT2A) gene in 11q23 are the most frequent rearrangements. Here, we report on the identification of a novel cryptic insertion, ins(11;X)(q23;q28q12), resulting in a translocation of the KMT2A gene in 11q23, leading to a KMT2A-FLNA fusion in a 13-month-old boy with de novo acute myelomonocytic leukemia, who died 38 days after diagnosis. The patient presented a complex karyotype 48∼49,Y,del(X)(q12),+del(X)(q12),+8,ins(11;X)(q23; q28q12),+19. The identified fusion gene was predicted to be out-of-frame (fusion of portions of KMT2A exon 11 with FLNA exon 11). However, RT-PCR experiments demonstrated that a potentially functional transcript was generated by alternative splicing where KMT2A exon 10 was spliced in-frame to the truncated FLNA exon 11. This case report helps to better understand the rare but potentially severe impact of KMT2A- FLNA fusions in infants with AML to improve prognostic stratification of therapy and clinical management.

Mutations in CCAAT/enhancer binding protein α (CEBPA) occur in 5-10% of cases of acute myeloid leukemia. CEBPA-double-mutated cases usually bear biallelic N- and C-terminal mutations and are associated with a favorable clinical outcome. Identification of CEBPA mutants is challenging because of the variety of mutations, intrinsic characteristics of the gene and technical issues. Several screening methods (fragment-length analysis, gene expression array) have been proposed especially for large-scale clinical use; although efficient, they are limited by specific concerns. We investigated the phenotypic profile of blast and maturing bone marrow cell compartments at diagnosis in 251 cases of acute myeloid leukemia. In this cohort, 16 (6.4%) patients had two CEBPA mutations, whereas ten (4.0%) had a single mutation. First, we highlighted that the CEBPA-double-mutated subset displays recurrent phenotypic abnormalities in all cell compartments. By mutational analysis after cell sorting, we demonstrated that this common phenotypic signature depends on CEBPA-double-mutated multi-lineage involvement. From a multidimensional study of phenotypic data, we developed a classifier including ten core and widely available parameters. The selected markers on blasts (CD34, CD117, CD7, CD15, CD65), neutrophil (SSC, CD64), monocytic (CD14, CD64) and erythroid (CD117) compartments were able to cluster CEBPA-double-mutated cases. In a validation set of 259 AML cases from three independent centers, our classifier showed excellent performance with 100% specificity and 100% sensitivity. We have, therefore, established a reliable screening method, based upon multidimensional analysis of widely available phenotypic parameters. This method provides early results and is suitable for large-scale detection of CEBPA-double-mutated status, allowing gene sequencing to be focused in selected cases.

The t(11;20)(p15;q11∼12) translocation is a very rare but recurrent cytogenetic aberration that occurs in myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). This translocation was shown to form a fusion gene between NUP98 at 11p15 and TOP1 at 20q12. Here, we describe a new case of de novo AML M2 with t(11;20) which was associated with another balanced translocation. An 81-year-old man was admitted to undergo salvage therapy for relapsed AML. G-banding and spectral karyotyping showed 46,XY,t(2;5)(q33;q31),t(11;20)(p15;q12)[20]. Expression of the NUP98/TOP1 fusion transcript was confirmed: NUP98 exon 13 was in-frame fused with TOP1 exon 8. The reciprocal TOP1/NUP98 fusion transcript was also detected: TOP1 exon 7 was fused with NUP98 exon 14. After achieving hematological complete remission, the karyotype converted to 46,XY,t(2;5)(q33;q31)[19]/46,sl,t(11;20)(p15;q12)[1]. FISH analysis demonstrated that the 5q31 breakpoint of t(2;5) was centromeric to EGR1. In all 10 cases described in the literature, the NUP98 exon 13/TOP1 exon 8 fusion transcript was expressed, indicating that it may be responsible for the pathogenesis of MDS/AML with t(11;20). On the other hand, the TOP1/NUP98 transcript was coexpressed in 4 cases of de novo AML, but not in 3 cases of therapy-related MDS. Thus, this reciprocal fusion may be associated with progression to AML.

Purpose Proton magnetic resonance spectroscopy (MRS) of the brain can detect 2-hydroxyglutarate (2HG), the oncometabolite produced in neoplasms harboring a mutation in the gene coding for isocitrate dehydrogenase ( IDH). We conducted a prospective longitudinal imaging study to determine whether quantitative assessment of 2HG by MRS could serve as a noninvasive clinical imaging biomarker for IDH-mutated gliomas. Patients and Methods 2HG MRS was performed in 136 patients using point-resolved spectroscopy at 3 T in parallel with standard clinical magnetic resonance imaging and assessment. Data were analyzed in patient cohorts representing the major phases of the glioma clinical course and were further subgrouped by histology and treatment type to evaluate 2HG. Histologic correlations were performed. Results Quantitative 2HG MRS was technically and biologically reproducible. 2HG concentration > 1 mM could be reliably detected with high confidence. During the period of indolent disease, 2HG concentration varied by less than ± 1 mM, and it increased sharply with tumor progression. 2HG concentration was positively correlated with tumor cellularity and significantly differed between high- and lower-grade gliomas. In response to cytotoxic therapy, 2HG concentration decreased rapidly in 1p/19q codeleted oligodendrogliomas and with a slower time course in astrocytomas and mixed gliomas. The magnitude and time course of the decrease in 2HG concentration and magnitude of the decrease in tumor volume did not differ between oligodendrogliomas treated with temozolomide or carmustine. Criteria for 2HG MRS were established to make a presumptive molecular diagnosis of an IDH mutation in gliomas technically unable to undergo a surgical procedure. Conclusion 2HG concentration as measured by MRS was reproducible and reliably reflected the disease state. These data provide a basis for incorporating 2HG MRS into clinical management of IDH-mutated gliomas.

Increasing prostate cancer incidence rates highlight the importance of more timely diagnosis with the ultimate aim of reducing cancer-specific mortality, while maintaining patients quality of life. Until recently, digital rectal examination and prostate-specific antigen have been used for diagnosis of prostate cancer. Recent advances in medical technologies and laboratory testing have led to introducing new cancer markers into clinical practice. The most highly demanded of them are the PCA-3, -2proPSA and Prostate Health Index. Despite the wide range of laboratory tests, a prostate biopsy with a subsequent morphological examination of biopsy tissue specimens remains the only way to definitively diagnose prostate cancer.

Development of bladder cancer (BC) involves accumulating several genetic alterations in somatic cells: point mutations, extended deletions in the localization of tumor suppressor genes, amplification of oncogenes, aberrant DNA methylation, changes in the expression pattern of regulatory RNAs and numerous structural genes. From all of the above, point mutations have the greatest potential as diagnostic markers, as they frequently occur in carcinogenesis, characterize initiation and further clonal evolution of malignancy and represent a change in DNA detectable by routine molecular genetic methods. If we look at the clinical classification of bladder cancer, 90% of the BC presented by urothelial carcinoma, 80% of patients had superficial and 20% - of muscle-invasive tumors. The differences in morphological classification, staging and prognosis of bladder cancer represent different pathogenic pathways of tumor development. Superficial bladder cancer develops through a stage of hyperplasia involving activation of mutations in the genes FGFR3, PIK3CA, HRAS, ERBB2, TERT and others. It is shown that frequent point mutations FGFR3, PIK3CA and TERT are present in the tumor cells in the urine sediment and can be considered as markers for non-invasive molecular genetic diagnosis of primary BC and for monitoring of disease recurrence. Muscle-invasive bladder cancer develops through the stages of dysplasia and carcinoma in situ, in which mutations initially occur in key suppressor genes (TP53 and RB1) and a number of chromatin remodeling genes. This leads to genomic instability and multiple chromosome aberrations that are subjected to selection in the further clonal evolution of tumors towards predominance of more malignant subclones. This review presents systematized information about the main mutations in BC carcinogenesis, their role in the primary tumor progression, metastasizing and role as a target for diagnosis and targeted therapy.

Glucocorticoid receptor (GR) is identified as a member of nuclear receptor family. To exert its biological action, the ligand bound GR is translocated from the cytoplasm into the nucleus by regulating transcriptional signals of related genes. In clinical practice, the effects of glucocorticoid are often mediated by GR signaling pathways. An increasing number of studies have indicated that GR signaling pathways play an essential role in the proliferation, invasion and prognosis of bladder cancer. Meanwhile, the new-generation selective GR activator improves its anti-tumor effects, and at the same time reduces the adverse reactions of hormones, which probably raises the prospect for the treatment of bladder cancer.

Human papillomaviruses (HPV) are responsible for the development of almost all cervical cancers. HPV is also found in 85% of anal cancer and in 50% of penile, vulvar, and vaginal cancers, and they are increasingly found in a subset of head and neck cancers, i.e., oropharyngeal squamous cell carcinomas (OPSCC). The model for how HPV causes cancer is derived from several decades of study on cervical cancer, and it is just presumed that this model is not only completely valid for cervical cancer but for all other HPV-driven cancers as well. Next-generation sequencing (NGS) has now provided the necessary tools to characterize genomic alterations in cancer cells and can precisely determine the physical status of HPV in those cells as well. We discuss recent discoveries from different applications of NGS in both cervical cancer and OPSCCs, including whole-genome sequencing and mate-pair NGS. We also discuss what NGS studies have revealed about the different ways that HPV can be involved in cancer formation, specifically comparing cervical cancer and OPSCC.

The tripartite motif-containing protein 11 (TRIM11), a member of the TRIM protein family, has attracted much attention because of its involvement in the development of the central nervous system. It has gained renewed focus because of its newly found function in promoting tumors. However, little is known about its role in hepatocellular carcinoma (HCC). In the present study, we found TRIM11 to be overexpressed in HCC tissues and cell lines. Downregulation of TRIM11 inhibited HCC cell proliferation and invasion in vitro and in vivo as well as suppressed the epithelial-mesenchymal transition (EMT) process. In addition, downregulation of TRIM11 decreased the protein expression levels of p-PI3K and p-Akt in HCC cells and thus inhibited activation of the PI3K/Akt signaling pathway. Based on these results, we suggest the importance of TRIM11 in HCC progression and the potential of TRIM11 as a therapeutic target for HCC.

DEAD (Asp-Glu-Ala-Asp) box protein 5 (DDX5), a prototypical member of the DEAD/H-box protein family, has been involved in several human malignancies. However, the expression and biological role of DDX5 in esophageal cancer (EC) remain largely unknown. In this study, we examined the role of DDX5 in regulating EC cell proliferation and tumorigenesis and explored its possible molecular mechanism. We found that DDX5 was overexpressed in human EC cell lines. In addition, knockdown of DDX5 significantly inhibited the proliferation of EC cells in vitro and the growth of EC xenografts in vivo. Knockdown of DDX5 also suppressed the migration/invasion and epithelial-to-mesenchymal transition (EMT) phenotype in EC cells. Furthermore, we observed that knockdown of DDX5 inhibited the expression of β-catenin, c-Myc, and cyclin D1 in EC cells. In conclusion, our findings provide the first evidence that siRNA-DDX5 inhibited the proliferation and invasion of EC cells through suppressing the Wnt/β-catenin signaling pathway. Therefore, DDX5 may be a novel potential therapeutic target for the prevention and treatment of EC.

Hepatocyte cell adhesion molecule (hepaCAM), a new type of CAM, belongs to the immunoglobulin superfamily. Recently, hepaCAM was reported to be implicated in cancer development, and many researchers investigated its biological function in the tumorigenesis of various cancers. However, what kind of role hepaCAM plays in colorectal cancer (CRC) remains unknown. In this study, we found that hepaCAM was downregulated in CRC tissues and cell lines. Overexpression of hepaCAM inhibited CRC cell proliferation, migration, and invasion in vitro. Furthermore, the tumorigenesis assay showed that increased expression of hepaCAM suppressed CRC tumor growth and metastasis in vivo. We also demonstrated that overexpression of hepaCAM reduced the protein expression levels of β-catenin, cyclin D1, and c-Myc, indicating its inhibitory effect on the Wnt/β-catenin signaling pathway. In conclusion, our study results suggest hepaCAM as a promising therapeutic target for CRC and provide a better understanding for the molecular basis of CRC progression.

CD147 is a transmembrane protein that can induce the expression and activity of matrix metalloproteinases (MMPs). Expression of CD147 has been shown to potentiate cell migration, invasion, and metastasis of cancer. In this study, the critical role of CD147 in metastasis was elucidated using CD147-overexpressing cholangiocarcinoma (CCA) cells in vitro and in vivo. The molecular mechanism, demonstrated herein, supported the hypothesis that metastasis increased in CD147-overexpressing cells. Five CD147-overexpressing clones (Ex-CD147) were established from a low CD147-expressing CCA cell line, KKU-055, using lentivirus containing pReceiver-Lenti-CD147. The metastatic capability was determined using the tail vein injection mouse model and an in vitro 3D invasion assay. Liver colonization was assessed using anti-HLA class I immunohistochemistry. Adhesion abilities, cytoskeletal arrangements, MMP activities, the expressions of adhesion molecules, and epithelial-mesenchymal transitional markers were analyzed. All Ex-CD147 clones exhibited a high CD147 expression and high liver colonization in the tail vein-injected mouse model, whereas parental cells lacked this ability. Ex-CD147 clones exhibited metastatic phenotypes (i.e., an increase in F-actin rearrangement) and cell invasion and a decrease in cell adhesion. The molecular mechanisms were shown to be via the induction of MMP-2 activity and enhancement of epithelial-mesenchymal transitions. An increase in mesenchymal markers Slug, vimentin, and N-cadherin, and a decrease in epithelial markers E-cadherin and claudin-1, together with suppression of the adhesion molecule ICAM-1, were observed in the Ex-CD147 clones. Moreover, suppression of CD147 expression using siCD147 in two CCA cell lines with high CD147 expression significantly decreased cell migration and invasion of these CCA cells. These findings emphasize the essential role of CD147 in CCA metastasis and suggest CD147 as a promising target for the effective treatment of CCA.

Transmembrane protein 45B (TMEM45B) is a member of the TMEM family of proteins and has been reported to be expressed abnormally in different kinds of human tumors. However, the biological function of TMEM45B in osteosarcoma remains unclear. The objective of this study was to investigate the role of TMEM45B in regulating the biological behavior of osteosarcoma cells. Our results demonstrated that the expression of TMEM45B at both the protein and mRNA levels was dramatically upregulated in human osteosarcoma cell lines. Knockdown of TMEM45B significantly suppressed the proliferation, migration, and invasion of U2OS cells in vitro. Mechanistically, knockdown of TMEM45B sharply downregulated the expression level of β-catenin, cyclin D1, and c-Myc in U2OS cells. Finally, knockdown of TMEM45B attenuated tumor growth in transplanted U2OS-derived tumors in nude mice. Taken together, our results demonstrated that TMEM45B plays an important role in regulating the proliferation, migration, and invasion of osteosarcoma cells and that its effects on proliferation and invasion were mediated partially through the Wnt/β-catenin signaling pathway. These observations support our belief that TMEM45B may serve as an oncogene in the development and progression of osteosarcoma.

Gliomas are the most common and aggressive type of primary adult brain tumors. Although GGNBP2 has previously been considered to be a tumor suppressor gene, little is known about the association between GGNBP2 and glioma. In this study, we clearly demonstrated that GGNBP2 was downexpressed in glioma tissues, and its downexpression is related to the pathological grade and overall survival of patients with gliomas. Overexpression of GGNBP2 suppressed the proliferation, migration, and invasion of glioma cells. Mechanistically, we demonstrated that the PI3K/Akt and Wnt/β-catenin signaling pathways were suppressed by GGNBP2 overexpression. In contrast, knockdown of GGNBP2 has precisely the opposite effect. Collectively, these data indicate that GGNBP2 shows tumor suppressive activity in human glioma cells and may stand out as a potential therapeutic target for glioma.

Pyroptosis is a type of proinflammatory programmed cell death mediated by caspase 1 activity and occurs in several types of eukaryotic tumor cells, including gliomas. MicroRNAs (miRNAs), small endogenous noncoding RNAs, have been demonstrated to be advantageous in glioma therapy. However, the question of whether miRNAs regulate pyroptosis in glioma remains unknown. The current study found that caspase 1 expression was substantially increased in both glioma tissues and glioma cell lines, U87 and T98G, while miR-214 expression was significantly downregulated. Luciferase reporter assay recognized caspase 1 as a target gene of miR-214. These findings demonstrate that miR-214 could inhibit cell proliferation and migration through the regulation of pyroptosis intermediated by caspase 1 in glioma U87 and T98G cells and may suggest a novel therapeutic for the intervention of glioma.

Spinal osteosarcoma (OS) has been proven to be more difficult to treat owing to potently malignant metastasis. The present study aimed to explore the functional role of microRNA (miR)-373 in cell growth and invasion of OS cells, as well as its underlying mechanism. The expression of miR-373 was analyzed in spinal OS tissues and cell lines. MG-63 cells were transfected with the miR-373 mimic or inhibitor and/or treated with the phosphoinositide 3-kinase (PI3K) (LY294002) inhibitor or Ras-related C3 botulinum toxin substrate 1 (Rac) guanosine triphosphate (GTPase) (NSC23766) inhibitor, and then the impact of miR-373 aberrant expression on cell growth and invasion was measured, along with the impact of overexpressing miR-373 on the expression of p53 and PI3K/AKT pathway-related proteins. We found that miR-373 was specifically upregulated in spinal OS tissues (p < 0.01) and OS cell lines (p < 0.01 or p < 0.001). Moreover, miR-373 expression was significantly associated with TNM stage (p = 0.035) and tumor size (p = 0.002). Overexpression of miR-373 promoted MG-63 cell viability, migration, invasion, and colony formation (all p < 0.05), while silencing of miR-373 and LY294002 exerted the opposite effects. Additionally, miR-373 overexpression downregulated p53 as well as its downstream targeted genes and orderly activated the PI3K/AKT-Rac1-JNK signaling pathway. In conclusion, miR-373 promotes growth and cellular invasion in OS cells by activating the PI3K/AKT-Rac1-JNK pathway. Therefore, miR-373 might be a candidate for molecular targeted therapy of spinal OS.

Some microRNAs (miRs) have been demonstrated to play promoting or tumor-suppressing roles in the development and progression of hepatocellular carcinoma (HCC). However, the regulatory mechanism of miR-98-5p in HCC still remains largely unclear. In the present study, our data showed that miR-98-5p was significantly downregulated in 84 cases of HCC tissues compared to the matched adjacent nontumor tissues. In addition, downregulation of miR-98-5p was associated with tumor size, portal vein tumor embolus, node metastasis, and clinical stage in HCC. HCC patients with low expression of miR-98-5p showed a shorter survival time compared with those with high miR-98-5p levels. Moreover, the expression of miR-98-5p was also reduced in HCC cell lines (HepG2, Hep3B, LM3, and SMCC7721) compared to the normal liver cell line THLE-3. Overexpression of miR-98-5p significantly decreased LM3 cell growth by inducing cell cycle arrest at the G1 stage and cell apoptosis. Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) was then identified as a novel target gene of miR-98-5p, and its protein expression was negatively regulated by miR-98-5p in LM3 cells. Overexpression of IGF2BP1 eliminated the effects of miR-98-5p overexpression on the proliferation, cell cycle, and apoptosis of LM3 cells. Finally, we found that IGF2BP1 was upregulated in HCC, and its expression was negatively correlated to miR-98-5p levels. In summary, we demonstrate that miR-98-5p could inhibit HCC cell proliferation while inducing cell apoptosis, partly at least, via inhibition of its target gene IGF2BP1, and we suggest that miR-98-5p may become a promising therapeutic candidate for HCC treatment.

Use of neoadjuvant chemotherapy (NACT) in locally advanced breast cancer (LABC) enables tumor reduction and conservative surgery. It is proposed in some studies that there may be an alteration in the hormonal receptor (HR) status and human epidermal growth factor receptor 2 (Her-2)/neu immune-expression following NACT.

Invasive lobular carcinoma (ILC) is the second most common type of breast cancer accounting for 5%-15% of all the breast cancer cases. The present study was performed on 171 breast cancer patients from Balochistan registered in CENAR (Center for Nuclear Medicine and Radiotherapy), Quetta.