MicroRNAs as a therapeutic target in IgA nephropathy in Indian population.

Immunoglobulin A nephropathy (IgAN) is the most frequent glomerular disease with rapid development to end stage renal disease, requiring renal replacement therapy. Genome-wide studies suggest geographical variations in genetic susceptibility to IgAN and disease progression. Specific 'candidate genes' were indicated to correlate with different functions that are involved in the pathogenesis of renal conditions. MicroRNAs (miRNAs/miRs) have a major role in mRNA degradation or translation repression, thereby regulating the expression of their target proteins. Previously, a small number of miRNAs were reported to have direct associations with IgAN. In the present study, new miRNAs linked to IgAN were identified in the Indian population. The miRNA was isolated from kidney biopsies of patients with IgAN (n=6) and healthy control tissue from patients with renal cell carcinoma (n=6). The sequencing results indicated that the miRNA percentage acquired from controls and patients with IgAN was 5.61 and 4.35%, respectively. From the results, 10 upregulated and 15 downregulated miRNAs were identified. Of the 25 differentially expressed miRNAs (DEMs), miR-181a-5p, miR-28-3p, let-7g-5p, miR-92a-3p and miR-30c-5p were not reported previously. Furthermore, Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses suggested that the target genes of the DEMs were mainly enriched in pathways such as cancer, ErbB signalling, proteoglycans in cancer, Hippo signalling and MAPK pathways. The newly identified miRNAs may impact the behaviour of tissues or IgA deposition by regulating signalling pathways, which forms a basis for future studies aimed at improving the diagnosis and care of patients with IgAN in the Indian community.

Fatty changes associated with N-Nitrosodiethylamine (DEN) induced hepatocellular carcinoma: a role of sonic hedgehog signaling pathway.

BACKGROUNDS AND AIMS: Hepatocellular Carcinoma (HCC) is the leading cause of cancer-related mortality across the world. Non-viral etiological factors including obesity and metabolic syndrome have now become prevalent cause of hepatocellular carcinoma. Sonic Hedgehog (SHH) pathway is activated in hepatocellular carcinoma but its role in regulation of lipogenic molecules during the hepatocarcinogenesis is not known. The aim of present study is to explore the role of SHH pathway in fatty changes associated with hepatocarcinogenesis at different stages and to further correlate the expression of SHH with lipogenic pathways. RESULTS: Our results demonstrated significant increase in lipidosis and fibrosis in DEN+CCl4 treated animals. It was simultaneously associated with the enhanced expression level of SHH, E2F1, adiponectin, and lipogenic molecules in DEN+CCl4 treated animals. These results were also corroborated with the similar findings in higher stage patients' biospecimens. METHODS: N-Nitrosodiethylamine (DEN) and Carbon TetraChloride (CCl4) induced hepatocellular acrcinoma model in male Wistar rats were established to study the expression level of SHH pathway and associated fatty changes during different stages of hepatocarcinogenesis. The expression levels of SHH, E2F1, and lipogenic molecules were checked at different stages of hepatocellular carcinoma. These results were further compared with biospecimens of hepatocellular carcinoma patients of different stages. CONCLUSIONS: Our results revealed an unknown aspect of SHH pathway in hepatocarcinogenesis via its control over lipogenesis. It gives insight into the lipogenic properties of DEN+CCl4 induced rodent hepatocarcinogenesis model and how SHH pathway operate to arbitrate this response.

The molecular connection of histopathological heterogeneity in hepatocellular carcinoma: A role of Wnt and Hedgehog signaling pathways.

BACKGROUND: Hepatocellular carcinoma (HCC) is leading cause of cancer-related mortality and is categorized among the most common malignancies around the world. It is a heterogeneous tumor, which shows significant degree of histopathological heterogeneity. Despite the apparent histopathological diversity there has been very little distinct correlation between histopathological features and molecular aberrations particularly when it comes to the expression level of Wnt and Hh pathway molecules. The role of Wnt and Hh pathways in relation to HCC behavior viz. histopathological heterogeneity and aggressiveness is not known. Determining the sequential molecular changes and associated histopathological characteristic during HCC initiation, promotion, and progression would probably lead to a better treatment and prognosis. METHODS: N-Nitrosodiethylamine (DEN) induced HCC model in male Wistar rats were established to study the expression level of Wnt and Hh pathway molecules during different stages of hepatocarcinogenesis. Their expression levels were checked at mRNA and protein levels at initiation, promotion, and progression stages of HCC. The expression levels of Wnt and Hh pathway molecules were correlated with biospecimens of HCC patients of different stages. RESULTS: In the present study we identified the comprehensive change in the expression pattern of Wnt and Hh pathway molecules in DEN induced rodent hepatocarcinogenesis model. Our results demonstrate that ß-catenin /CTNNB1 plays important role in tumor initiation and promotion by stimulating tumor cell proliferation. The activated Wnt signaling in early stage of HCC is associated with well-differentiated histological pattern. The Hh activity although activated during the initiation stage but is significantly increased during the early promotion stage of hepatocarcinogenesis. The increased activity of both Wnt & Hh pathways during promotion stage is associated with moderately-differentiated histological pattern and was simultaneously linked with an increased expression of MMP9. Furthermore, our data demonstrated that during the progression stage Wnt pathway is modestly down-regulated but the Hh pathway activity sustained which in turn is associated with aggressive and invasive phenotype and poorly-differentiated histopathology. CONCLUSION: Our data uncovers the grade related expression of Wnt and Hh pathway molecules and the potential utility of these molecular signatures in daily clinical practice is to decide best therapy according to patients characteristic. Additionally, our data offer insight into the interaction between Wnt and Hh pathways which triggers HCC development and progression.

α-Lipoic acid inhibits the migration and invasion of breast cancer cells through inhibition of TGFß signaling.

AIMS: Invasion and metastasis are the main cause of mortality in breast cancer. Hence, novel therapeutic interventions with high specificity toward invasion and metastasis are necessary. α-Lipoic acid showed antiproliferative and cytotoxic effects on several cancers including breast cancer. However, the effect of lipoic acid on breast cancer metastasis remains unclear. MAIN METHODS: In the present study, we examined the effects of lipoic acid on the migration and invasion of MDA-MB-231 and 4T1 breast cancer cells. KEY FINDINGS: Our data showed that lipoic acid effectively inhibited the colony forming ability of highly invasive MDA-MB-231 and 4T1 cells. Moreover, the nontoxic concentrations of lipoic acid significantly reduced the migration of breast cancer cells. Lipoic acid also inhibited the TGFß-induced angiopoietin-like 4 (ANGPTL4) expression and reduced the activity of matrix metalloproteinase-9 (MMP-9), an enzyme involved in invasion and metastasis, in both the cell lines. The inhibition of cell migration by lipoic acid is accompanied by the downregulation of FAK, ERK1/2 and AKT phosphorylation, and inhibition of nuclear translocation of ß-catenin. SIGNIFICANCE: Our data demonstrated that lipoic acid inhibited the migration and invasion of metastatic breast cancer cells at least in part through inhibiting ERK1/2 and AKT signaling. Thus, our findings show that the inhibition of TGFß signaling is a potential mechanism for the anti-invasive effects of lipoic acid.

Hepatocellular carcinoma treatment: hurdles, advances and prospects.

Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related mortality and is particularly refractory to the available chemotherapeutic drugs. Among various etiologies of HCC, viral etiology is the most common, and, along with alcoholic liver disease and nonalcoholic steatohepatitis, accounts for almost 90% of all HCC cases. HCC is a heterogeneous tumor associated with multiple signaling pathway alterations and its complex patho-physiology has made the treatment decision challenging. The potential curative treatment options are effective only in small group of patients, while palliative treatments are associated with improved survival and quality of life for intermediate/advanced stage HCC patients. This review article focuses on the currently available treatment strategies and hurdles encountered for HCC therapy. The curative treatment options discussed are surgical resection, liver transplantation, and local ablative therapies which are effective for early stage HCC patients. The palliative treatment options discussed are embolizing therapies, systemic therapies, and molecular targeted therapies. Besides, the review also focuses on hurdles to be conquered for successful treatment of HCC and specifies the future prospects for HCC treatment. It also discusses the multi-modal approach for HCC management which maximizes the chances of better clinical outcome after treatment and identifies that selection of a particular treatment regimen based on patients' disease stage, patients' ages, and other underlying factors will certainly lead to a better prognosis.