Abstract
The expression of RNA polymerase II subunit 3 (Rpb3) was found frequent up-regulation in Hepatocellular carcinoma (HCC) tumors. Significant associations could also be drawn between increased expressions of Rpb3 and advance HCC staging and shorter disease-free survival of patients. Overexpression of Rpb3 increased HCC cell proliferation, migratory rate and tumor growth in nude mice, whereas suppression of Rpb3 using shRNA inhibited these effects. For mechanism study, we found that Rpb3 bound directly to Snail, downregulated E-cadherin, induced HCC cells epithelial-mesenchymal transition (EMT). In particular, N-terminus of Rpb3 blocked Rpb3 binding to Snail, inhibited Rpb3-high-expression HCC cells proliferation, migration, tumor growth in nude mice, and also inhibited DEN-induced liver tumorigenesis. Furthermore, N-terminus of Rpb3 did not inhibit normal liver cells or Rpb3-low-expression HCC cells proliferation. These findings suggest that N-terminus of Rpb3 selectively inhibits Rpb3-high-expression HCC cells proliferation. N-terminus of Rpb3 may be useful in treating patients diagnosed with Rpb3-high-expression HCC.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common solid tumor worldwide and the third leading fetal cancer [1]
We showed that RNA polymerase II subunit 3 (Rpb3) expression is frequently up-regulated in HCC (51.24%), in advanced stage of HCC (Stage IV, 72.63%), and there was a positive correlation between Rpb3 expression and advanced clinicopatological features
Functional analysis through gain- or loss-of-function studies showed that Rpb3-overexpression enhanced HCC cell proliferation, migration and in vivo tumor growth, whereas Rpb3knockdown using shRNA inhibited HCC cell proliferation, migration and in vivo tumor growth
Summary
Hepatocellular carcinoma (HCC) is the fifth most common solid tumor worldwide and the third leading fetal cancer [1]. Three RNA polymerases play fundamental roles in the cell. RNA polymerase I and III transcribe ribosomal DNA, tRNAs and small nuclear RNA genes. RNA Pol II transcribes protein coding genes and some small nuclear RNA genes [2]. This enzyme consists of 12 different subunits and is subjected to many controls, including initiation, elongation and termination of mRNA transcription.[3] little is known about the specific functions of its individual subunits, associations between subunits, or possible contacts between subunits and transcription factors. Rpb expression is regulated during cell differentiation, it binds to myogenic factor, ATF4 and IGF-binding protein (IGFBP)-3, and increases their transactivation activity [6,7,8]. It would be very interesting to explore the roles of individual subunits besides their function in RNA polymerases complex
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