Research Projects

Rationale of the Research Hepatocellular carcinoma (HCC) is an advanced stage of a common, aggressive, heterogenous, and generally incurable form of liver cancer. HCC ranks 6th in cancer occurrence worldwide and is the third one associated with cancer-related deaths (1). Risk factors include viral hepatitis infection, chronic alcohol consumption, cirrhosis, diabetes mellitus, NAFLD, and NASH (2). In Southeast Asia, 22% of men and 9% of female cancer patients were affected by HCC. In HCC, not only every patient but each tumour site of the same patient may be genetically unique, hence the different response towards treatments, eventually making the treatment more difficult. Also, HCC is diagnosed at a very advanced stage due to the lack of an early detectable biomarker. Therefore, targeting more than one signalling pathway together with different drug combinations, along with the investigation of early biomarkers for early diagnosis of HCC, is highly warranted. In HCC oncogenesis, multiple signalling pathways viz. WNT–β-catenin, Hedgehog, Hippo, PI3K/AKT/mTOR pathway, receptor tyrosine kinases, are altered and play a central role (3, 4). Among all, mTOR pathway was found to be constitutively activated in 40% of HCC cases and associated with aggressive tumour progression and shorter survival of HCC patients (5). mTOR hyperactivation is sufficient to cause HCC in mice. Therefore, targeting the mTOR pathway will be promising in therapeutic control of HCC. Ribosomes are composed of ribosomal proteins and rRNA forming the ribonucleoprotein complexes required for protein translation. Ribosome biogenesis is a major energy-consuming and highly orchestrated process. Its dysregulation or abrupt expression of riboproteins is associated with oncogenesis (6,7). DDX5/DDX17 plays a crucial role in ribosome biogenesis and remodeling of ribonucleoprotein complexes. They also co-activate expression of various transcription factors, which is regulated by post-translational modifications (8). Abnormal expression of DDX5/DDX17 or any unusual PTMs leads to tumorigenesis (9). DDX5 promotes HCC by activating the PI3K/Akt signalling pathway, whereas DDX17 promotes HCC by inhibiting Klf4 transcriptional activity (10,11). However, several other studies state DDX5/DDX17 as a suppressor of tumorigenesis in HCC (12,13). Henceforth, investigating the detailed role of DDX5/DDX17 in ribosome biogenesis and translation regulation in HCC models and human samples is the need of the hour. Hypothesis DDX5/DDX17 have a multifaceted role in HCC pathogenesis. Preliminary observations from Shetty Lab, ACTREC report a novel interaction of DDX5/17 with ribosomes in mTOR-hyperactive HCC cell line. We hypothesize that DDX5/17 might be oncogenic under hyperactive mTOR conditions and modulating the protein synthesis in HCC cell lines, mouse models, and human patient samples. AIM To decipher the role of DDX5/DDX17 in the regulation of protein synthesis and ribosome biogenesis in HCC.