Leprosy, an infectious disease caused by Mycobacterium leprae , affects millions of people worldwide. However, little is known regarding its molecular pathophysiological mechanisms. In this study, a comprehensive assessment of human mRNA was performed on leprosy skin lesions by using DNA chip microarrays, which included the entire spectrum of the disease along with its reactional states. Sixty-six samples from leprotic lesions (10TT, 10BT, 10BB, 10BL, 4LL, 14R1, and 10R2) and nine skin biopsies from healthy individuals were used as controls (CC) (ages ranged from 06 to 83 years, 48 were male and 29 female). The evaluation identified 1580 differentially expressed mRNAs [Fold Change ( FC ) ≥ 2.0, p ≤ 0.05] in diseased lesions vs. healthy controls. Some of these genes were observed in all forms of the disease (CD2, CD27, chit1, FA2H, FAM26F, GZMB, MMP9, SLAMF7, UBD) and others were exclusive to reactional forms (Type “1” reaction: GPNMB, IL1B, MICAL2, FOXQ1; Type “2” reaction: AKR1B10, FAM180B, FOXQ1, NNMT, NR1D1, PTX3, TNFRSF25). In literature, these mRNAs have been associated with numerous pathophysiological processes and signaling pathways and are present in a large number of diseases. The role of these mRNAs maybe studied in the context of developing new diagnostic markers and therapeutic targets for leprosy.
Lymphovascular invasion (LVI) and histologic grade are clinical parameters of high prognostic value in breast cancer and indicate the level of tumor aggressiveness. Many studies have focused on the association of breast cancer subtypes with gene expression and chromosomal profiles, but considerably less genomic information is available regarding traditional prognostic factors such as histologic grade and LVI. We studied by array-CGH a group of 57 invasive ductal carcinomas of the breast to outline the DNA copy number aberration (CNA) profile linked to high histologic grades and LVI. Selected CNAs were validated using real-time quantitative PCR (qPCR). Furthermore, gene expression analysis was performed in a subset of 32 of these tumors, and findings were integrated with array-CGH data. Our findings indicated an accumulation of genomic alterations in high-grade breast tumors compared to low-grade samples. Grade III tumors showed higher number of CNAs and larger aberrations than low-grade tumors and displayed a wide range of chromosomal aberrations, which were mainly 5p, 8q, 10p, 17q12, and 19 gains, and 3p, 4, 5q proximal, 9p, 11p, 18q, and 21 losses. The presence of LVI, a well-established prognostic marker, was not significantly associated with increased genomic instability in comparison to breast tumors negative for LVI, considering the total number of chromosomal alterations. However, a slightly increase in the frequency of specific alterations could be detected in LVI-positive group, such as gains at 5p, 16p, 17q12, and 19, and losses at 8p, 11q, 18q, and 21. Three newly reported small-scale rearrangements were detected in high-risk tumors (LVI-positive grade III) harboring putative breast cancer genes (amplicons at 4q13.3 and 11p11.2, and a deletion at 12p12.3). Furthermore, gene expression analysis uncovered networks highlighting S100A8, MMP1, and MED1 as promising candidate genes involved in high-grade and LVI-positive tumors. In summary, a group of genomic regions could be associated with high-risk tumors, and expression analysis pinpointed candidate genes deserving further investigation. The data has shed some light on the molecular players involved in two highly relevant prognostic factors and may further add to the understanding of the mechanisms of breast cancer aggressiveness.Electronic supplementary materialThe online version of this article (doi:10.1007/s13277-014-2786-z) contains supplementary material, which is available to authorized users.
Leprosy, a chronic infectious disease caused by Mycobacterium leprae, is a major public health problem in poor and developing countries of the Americas, Africa, and Asia. MicroRNAs (miRNAs), which are small non-coding RNAs (18–24 nucleotides), play an important role in regulating cell and tissue homeostasis through translational downregulation of messenger RNAs (mRNAs). Deregulation of miRNA expression is important for the pathogenesis of various neoplastic and non-neoplastic diseases and has been the focus of many publications; however, studies on the expression of miRNAs in leprosy are rare. Herein, an extensive evaluation of differentially expressed miRNAs was performed on leprosy skin lesions using microarrays. Leprosy patients, classified according to Ridley and Jopling’s classification or reactional states (R1 and R2), and healthy controls (HCs) were included. Punch biopsies were collected from the borders of leprosy lesions (10 tuberculoid, 10 borderline tuberculoid, 10 borderline borderline, 10 borderline lepromatous, 4 lepromatous, 14 R1, and 9 R2) and from 9 HCs. miRNA expression profiles were obtained using the Agilent Microarray platform with miRBase, which consists of 1,368 Homo sapiens (hsa)-miRNA candidates. TaqMan quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) was used to validate differentially expressed miRNAs. Sixty-four differentially expressed miRNAs, including 50 upregulated and 14 downregulated (fold change ≥2.0, p-value ≤ 0.05) were identified after comparing samples from patients to those of controls. Twenty differentially expressed miRNAs were identified exclusively in the reactional samples (14 type 1 and 6 type 2). Eight miRNAs were validated by RT-PCR, including seven upregulated (hsa-miR-142-3p, hsa-miR-142-5p, hsa-miR-146b-5p, hsa-miR-342-3p, hsa-miR-361-3p, hsa-miR-3653, and hsa-miR-484) and one downregulated (hsa-miR-1290). These miRNAs were differentially expressed in leprosy and several other diseases, especially those related to the immune response. Moreover, the integration of analysis of validated mi/mRNAs obtained from the same samples allowed target pairs opposite expression pattern of hsa-miRNA-142-3p and AKR1B10, hsa-miRNA-342-3p and FAM180b, and hsa-miRNA-484 and FASN. This study identified several miRNAs that might play an important role in the molecular pathogenesis of the disease. Moreover, these deregulated miRNAs and their respective signaling pathways might be useful as therapeutic markers, therapeutic targets, which could help in the development of drugs to treat leprosy.
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