Gene expression profiling, pathway analysis and subtype classification reveal molecular heterogeneity in hepatocellular carcinoma and suggest subtype specific therapeutic targets

Abstract

A very low 5-year survival rate among hepatocellular carcinoma (HCC) patients is mainly due to lack of early stage diagnosis, distant metastasis and high risk of postoperative recurrence. Hence ascertaining novel biomarkers for early diagnosis and patient specific therapeutics is crucial and urgent. Here, we have performed a comprehensive analysis of the expression data of 423 HCC patients (373 tumors and 50 controls) downloaded from The Cancer Genome Atlas (TCGA) followed by pathway enrichment by gene ontology annotations, subtype classification and overall survival analysis. The differential gene expression analysis using non-parametric Wilcoxon test revealed a total of 479 up-regulated and 91 down-regulated genes in HCC compared to controls. The list of top differentially expressed genes mainly consists of tumor/cancer associated genes, such as AFP, THBS4, LCN2, GPC3, NUF2, etc. The genes over-expressed in HCC were mainly associated with cell cycle pathways. In total, 59 kinases associated genes were found over-expressed in HCC, including TTK, MELK, BUB1, NEK2, BUB1B, AURKB, PLK1, CDK1, PKMYT1, PBK, etc. Overall four distinct HCC subtypes were predicted using consensus clustering method. Each subtype was unique in terms of gene expression, pathway enrichment and median survival. Conclusively, this study has exposed a number of interesting genes which can be exploited in future as potential markers of HCC, diagnostic as well as prognostic and subtype classification may guide for improved and specific therapy.

Role of cyclin‐dependent kinases (CDKs) in hepatocellular carcinoma: Therapeutic potential of targeting the CDK signaling pathway

“…Overexpression of CDK1 is associated with poor clinicopathologic features and is predictive of recurrence. This study also showed that CDK1 is a crucial G 2 –M modulator in cell cycle progression and cell proliferation of HCC . In the case of HCC, CDK1 is overactive when compared to comparable non‐tumor tissues .…”

“…This study also showed that CDK1 is a crucial G 2 -M modulator in cell cycle progression and cell proliferation of HCC. 42 In the case of HCC, CDK1 is overactive when compared to comparable nontumor tissues. 23 As expected, HCC tissues consistently show elevated CDK1 expression in western blot and real- Figure 1 Cell cycle-associated development of hepatocellular carcinoma (HCC).…”

miR‐584‐5p regulates hepatocellular carcinoma cell migration and invasion through targeting KCNE2

“…Cancer cell is characterized as uncontrolled cell growth, migration, and invasion that resulted from abnormal expression of many protein‐coding genes and abnormal activation signaling pathways (Agarwal, Narayan, Bhattacharyya, Saraswat, & Tomar, ; Jin et al, ). In addition to protein‐coding genes, noncoding RNAs including circular RNAs and microRNAs (miRNAs) are also reported to involve in HCC carcinogenesis (Xiong et al, ).…”

Family history of liver cancer may modify the association between HBV infection and liver cancer in a Chinese population

“…In our study, having family history of liver cancer showed four times the risk of liver cancer, and if it was from first‐degree relative, the risk increase was five times, which was stronger than the associations reported in former observations . Inheritance is believed to play a role in liver carcinogenesis and genetic epidemiologic studies kept searching for and reporting susceptible loci . Meanwhile, family‐aggregated environmental exposures also increased the risk, and the associations between aflatoxin intake though mildew‐contaminated food, unsafe raw water and liver cancer risk were confirmed in this study and previous literature …”