Differential combinatorial regulatory network analysis related to venous metastasis of hepatocellular carcinoma

Abstract

BackgroundHepatocellular carcinoma (HCC) is one of the most fatal cancers in the world, and metastasis is a significant cause to the high mortality in patients with HCC. However, the molecular mechanism behind HCC metastasis is not fully understood. Study of regulatory networks may help investigate HCC metastasis in the way of systems biology profiling.MethodsBy utilizing both sequence information and parallel microRNA(miRNA) and mRNA expression data on the same cohort of HBV related HCC patients without or with venous metastasis, we constructed combinatorial regulatory networks of non-metastatic and metastatic HCC which contain transcription factor(TF) regulation and miRNA regulation. Differential regulation patterns, classifying marker modules, and key regulatory miRNAs were analyzed by comparing non-metastatic and metastatic networks.ResultsGlobally TFs accounted for the main part of regulation while miRNAs for the minor part of regulation. However miRNAs displayed a more active role in the metastatic network than in the non-metastatic one. Seventeen differential regulatory modules discriminative of the metastatic status were identified as cumulative-module classifier, which could also distinguish survival time. MiR-16, miR-30a, Let-7e and miR-204 were identified as key miRNA regulators contributed to HCC metastasis.ConclusionIn this work we demonstrated an integrative approach to conduct differential combinatorial regulatory network analysis in the specific context venous metastasis of HBV-HCC. Our results proposed possible transcriptional regulatory patterns underlying the different metastatic subgroups of HCC. The workflow in this study can be applied in similar context of cancer research and could also be extended to other clinical topics.

miR-204 Inhibits Epithelial to Mesenchymal Transition by Targeting Slug in Intrahepatic Cholangiocarcinoma Cells

“…Downregulation of miR-204 is a frequent event in several cancers [20,21,22,23,24,25]. Recently, mounting evidence indicate that miR-204 play crucial roles in tumor invasion and metastasis.…”

“…miR-204 has been shown to be down-regulated and serve as a potential tumor suppressor in several distinct cancer types including endometrial cancer, malignant peripheral nerve sheath tumors, gastric cancer, glioma, and hepatocellular carcinoma [20,21,22,23,24,25]. However, the role of miR-204 in ICC progression and the molecular mechanisms by which miR-204 exerts its functions remain largely unknown.…”

Deregulation of microRNA expression in peripheral blood mononuclear cells from patients with HCV-related malignancies

“…Only two previous papers have speculated about the role of miR-16 expression in HCC: Qu et al [27] reported significantly lower levels of this microRNA in the serum of HCC patients compared to controls, while Zeng et al [28] attributed to it the ability of HCC to generate metastasis through repression of NOTCH signaling cascade. The data about the miR-16/HCC issue are scarce and conflicting, and we could not confirm any of the previously described scenarios since no aberrant expression of miR-16 was detected in our HCC cohort.…”

Genomics in 2012: challenges and opportunities in the next generation sequencing era

“…The authors showed that BCmicrO could outperform each individual algorithm measured by both sensitivity and specificity. Zeng et al, [19] demonstrated an integrative approach to studying differential combinatorial regulatory networks in venous metastasis of hepatocellular carcinoma. Both the microRNA and transcription factor regulations are integrated in their network analysis.…”