Identification of Key Deregulated RNA-Binding Proteins in Pancreatic Cancer by Meta-Analysis and Prediction of Their Role as Modulators of Oncogenesis.

ORIGINAL RESEARCH published: 29 November 2021 doi: 10.3389/fcell.2021.713852 Identification of Key Deregulated RNA-Binding Proteins in Pancreatic Cancer by Meta-Analysis and Prediction of Their Role as Modulators of Oncogenesis Moumita Mukherjee 1 and Srikanta Goswami 1,2* 1 Edited by: Sridhar Muthusami, Karpagam Academy of Higher Education, India Reviewed by: Eduardo Castañeda Saucedo, Autonomous University of Guerrero, Mexico Yi Pan, China Pharmaceutical University, China Dinesh Babu Somasundaram, University of Oklahoma Health Sciences Center, United States *Correspondence: Srikanta Goswami Specialty section: This article was submitted to Molecular and Cellular Oncology, a section of the journal Frontiers in Cell and Developmental Biology Received: 24 May 2021 Accepted: 04 November 2021 Published: 29 November 2021 Citation: Mukherjee M and Goswami S (2021) Identification of Key Deregulated RNABinding Proteins in Pancreatic Cancer by Meta-Analysis and Prediction of Their Role as Modulators of Oncogenesis. Front. Cell Dev. Biol. 9:713852. doi: 10.3389/fcell.2021.713852 National Institute of Biomedical Genomics, Kalyani, India, 2Regional Centre for Biotechnology, Faridabad, India RNA-binding proteins (RBPs) play a significant role in multiple cellular processes with their deregulations strongly associated with cancer. However, there are not adequate evidences regarding global alteration and functions of RBPs in pancreatic cancer, interrogated in a systematic manner. In this study, we have prepared an exhaustive list of RBPs from multiple sources, downloaded gene expression microarray data from a total of 241 pancreatic tumors and 124 normal pancreatic tissues, performed a meta-analysis, and obtained differentially expressed RBPs (DE-RBPs) using the Limma package of R Bioconductor. The results were validated in microarray datasets and the Cancer Genome Atlas (TCGA) RNA sequencing dataset for pancreatic adenocarcinoma (PAAD). Pathway enrichment analysis was performed using DE-RBPs, and we also constructed the protein–protein interaction (PPI) network to detect key modules and hub-RBPs. Coding and noncoding targets for top altered and hub RBPs were identified, and altered pathways modulated by these targets were also investigated. Our metaanalysis identified 45 upregulated and 15 downregulated RBPs as differentially expressed in pancreatic cancer, and pathway enrichment analysis demonstrated their important contribution in tumor development. As a result of PPI network analysis, 26 hub RBPs were detected and coding and noncoding targets for all these RBPs were categorized. Functional exploration characterized the pathways related to epithelial-tomesenchymal transition (EMT), cell migration, and metastasis to emerge as major pathways interfered by the targets of these RBPs. Our study identified a unique metasignature of 26 hub-RBPs to primarily modulate pancreatic tumor cell migration and metastasis in pancreatic cancer. IGF2BP3, ISG20, NIP7, PRDX1, RCC2, RUVBL1, SNRPD1, PAIP2B, and SIDT2 were found to play the most prominent role in the regulation of EMT in the process. The findings not only contribute to understand the biology of RBPs in pancreatic cancer but also to evaluate their candidature as possible therapeutic targets. Keywords: RNA-binding protein, pancreatic cancer, meta-analysis, epithelial-to-mesenchymal transition, target RNAs Frontiers in Cell and Developmental Biology | www.frontiersin.org 1 November 2021 | Volume 9 | Article 713852 Mukherjee and Goswami RBPs Modulate EMT in Pancreatic Cancer BACKGROUND cancer progression by means of cell proliferation and viability (Jin et al., 2016; Fan et al., 2017). Ribosomal proteins control tumor suppression via activation of p53, and deletion (43% of tumors) and mutation in genes encoding ribosomal proteins such as RPL22 are evidenced in several cancer types such as acute lymphoblastic leukemia (Sloan et al., 2013; Pelletier et al., 2018; Lessard et al., 2019). There are evidences of some onco-ribosomes as well like RPL10-R98S mutation in T-cell leukemia mimicking the oncogenic JAK-STAT pathway (Sulima et al., 2017; Girardi et al., 2018). Recent studies have corroborated that RBPs are highly predominant and ubiquitously expressed than any other regulatory elements throughout the cell (Wang et al., 2018). But as opposed to other cancer types, dysregulation of RBPs in the case of pancreatic cancer is not much worked out. With the recent advancement of knowledge about the multifaceted role of RBPs in cancer progression and keeping in mind the aggressive nature of pancreatic cancer, the disparity of RBPs in pancreatic cancer development needs to be explored. Here, at the beginning, we have performed a meta-analysis to identify the differentially expressed RBPs in pancreatic cancer and validated them in a separate validation dataset as well as in the Human Protein Atlas (Uhlén et al., 2015). This was followed by the identification of “hub” RBPs, finding out their coding and noncoding targets, and exploration of biological processes supposed to be altered by the deregulation of both the RBPs and their targets. Our discovery of RBPs getting involved in important oncogenic activities not only contributes to the existing knowledge but also opens up immense therapeutic possibilities. Pancreatic cancer is one of the most morbid cancer types worldwide and is mostly diagnosed at a very advanced stage with a 5-year survival rate of 8.2% (Gordon-Dseagu et al., 2018). Recent studies have identified several mutations to be predominant in different pancreatic cancer subtypes, and about 80% of these mutations are found to be sporadic (Feldmann et al., 2007; McGuigan et al., 2018). Pancreatic cancer is a heterogeneous disease with aberrant gene expression patterns like any other cancer. Therefore, in order to understand the biology of the disease, altered regulatory events need to be portrayed at the level of gene to RNA to protein to signaling pathways of the cell. After the expression of the genes, the roadway to the functionality of the transcripts is highly regulated at the posttranscriptional and translational level. RNA-binding proteins (RBPs) are an integral part of this regulatory machinery participating in all the cellular processes. RBPs exert multi-functionality in directing the fate of the transcripts such as splicing, stability, translocation, translation, and decay (Neelamraju et al., 2015). A transcript interacts with different RBPs at different stages of life, and its fate and functionality is decided accordingly. Canonical RBPs bind to the RNAs in a sequence-specific manner with the help of RNA-binding domains (RBDs) and form dynamic ribonucleoprotein (RNP) complexes to execute the regulatory function. RBPs can bind at the coding region of the mRNA, but it is more prevalent in the regulatory elements of the RNA such as the 5′ and 3′ untranslated regions (UTRs) and in the alternative UTRs of mRNA isoforms during RNA pr (...truncated)