ABSTRACT
Pancreatic cancer remains a grueling disease that is projected to become the second-deadliest cancer in the next decade. Standard treatment of pancreatic cancer is chemotherapy, which mainly targets the differentiated population of tumor cells; however, it paradoxically sets the roots of tumor relapse by the selective enrichment of intrinsically chemoresistant pancreatic cancer stem cells that are equipped with an indefinite capacity for self-renewal and differentiation, resulting in tumor regeneration and an overall anemic response to chemotherapy. Crosstalk between pancreatic tumor cells and the surrounding stromal microenvironment is also involved in the development of chemoresistance by creating a supportive niche, which enhances the stemness features and tumorigenicity of pancreatic cancer cells. In addition, the desmoplastic nature of the tumor-associated stroma acts as a physical barrier, which limits the intratumoral delivery of chemotherapeutics. In this review, we mainly focus on the transforming growth factor beta 1 (TGFB1)/inhibin subunit beta A (INHBA) homodimer/Nodal-SMAD2/3 signaling network in pancreatic cancer as a pivotal central node that regulates multiple key mechanisms involved in the development of chemoresistance, including enhancement of the stem cell-like properties and tumorigenicity of pancreatic cancer cells, mediating cooperative interactions between pancreatic cancer cells and the surrounding stroma, as well as regulating the deposition of extracellular matrix proteins within the tumor microenvironment.
Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Pancreatic Ductal/drug therapy , Drug Resistance, Neoplasm , Gene Expression Regulation, Neoplastic/drug effects , Molecular Targeted Therapy , Pancreatic Neoplasms/drug therapy , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/pathology , Humans , Inhibin-beta Subunits/antagonists & inhibitors , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Nodal Protein/antagonists & inhibitors , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Signal Transduction , Smad2 Protein/antagonists & inhibitors , Smad3 Protein/antagonists & inhibitors , Transforming Growth Factor beta1/antagonists & inhibitors , Tumor MicroenvironmentABSTRACT
LARP1 is an oncogenic RNA-binding protein required for ribosome biogenesis and cancer cell survival. From published in vitro studies, there is disparity over which of two different LARP1 protein isoforms (termed the long LI-LARP1 and short SI-LARP1) is the canonical. Here, after conducting a series of biochemical and cellular assays, we conclude that LI-LARP1 (NM_033551.3 > NP_056130.2) is the dominantly expressed form. We observe that SI-LARP1 (NM_015315.5> NP_056130.2) is epigenetically repressed and that this repression is evolutionarily conserved in all but a small subclade of mammalian species. As with other LARP family members, there are multiple potential LARP1 mRNA isoforms that appear to be censored within the nucleus. The capacity of the cell to modulate splicing and expression of these apparently 'redundant' mRNAs hints at contextually specific mechanisms of LARP1 expression.
Subject(s)
Autoantigens/genetics , Gene Expression Regulation, Neoplastic , Ribonucleoproteins/genetics , Alternative Splicing , Amino Acid Sequence , Autoantigens/chemistry , Autoantigens/metabolism , Cell Line, Tumor , DNA Methylation , Gene Silencing , Humans , Multigene Family , Organ Specificity , Promoter Regions, Genetic , Protein Binding , Protein Isoforms/genetics , Protein Isoforms/metabolism , RNA/genetics , RNA/metabolism , RNA-Binding Proteins/chemistry , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Ribonucleoproteins/chemistry , Ribonucleoproteins/metabolism , SS-B AntigenABSTRACT
The clinical efficacy and durability of KRASG12C-targeted therapies are limited by the development of resistance mechanisms. Here, we provide a review of recent KRASG12C-targeted therapy and immunotherapy-unifying strategies that utilize covalently modified peptide/MHC class I complexes as tumor-specific neoantigens to tag drug-resistant cancer cells for destruction with hapten-based immunotherapeutics.
Subject(s)
Neoplasms , Proto-Oncogene Proteins p21(ras) , Humans , Mutation , Neoplasms/therapy , Treatment Outcome , ImmunotherapyABSTRACT
RNA-binding proteins (RBPs) and noncoding (nc)RNAs (such as microRNAs, long ncRNAs, and others) cooperate within a post-transcriptional network to regulate the expression of genes required for many aspects of cancer behavior including its sensitivity to chemotherapy. Here, using an RBP-centric approach, we explore the current knowledge surrounding contributers to post-transcriptional gene regulation (PTGR) in ovarian cancer and identify commonalities that hint at the existence of an evolutionarily conserved core PTGR network. This network regulates survival and chemotherapy resistance in the contemporary context of the cancer cell. There is emerging evidence that cancers become dependent on PTGR factors for their survival. Further understanding of this network may identify innovative therapeutic targets as well as yield crucial insights into the hard-wiring of many malignancies, including ovarian cancer. WIREs RNA 2018, 9:e1432. doi: 10.1002/wrna.1432 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications Translation > Translation Mechanisms RNA in Disease and Development > RNA in Disease.