Abstract
Simple SummaryWith pancreatic cancer incidence constantly rising, constituting one of the most lethal type of cancers worldwide, the need for discovering novel therapeutic targets and approaches becomes of the utmost importance. Meanwhile, modern eating habits, hyperadiposity, mutational burden affecting core signaling pathways and the unique tumor microenvironment of pancreatic cancer tissues intermingle and form a disease that is lethal and hard to treat. The importance of HuR in pancreatic cancer has repeatedly been observed and represents a key molecule in pancreatic carcinogenesis and chemoresistance. Therefore, creating and obtaining new therapeutic skills against HuR protein could prove to be the answer to pancreatic cancer therapy.Pancreatic cancer is set to become the most lethal and common type of cancer worldwide. This is partly attributed to the mutational burden that affects core signaling pathways and the crosstalk of tumor cells with their surrounding microenvironment, but it is also due to modern eating habits. Hyperadiposity along with the constant rise in metabolic syndrome’s incidence contribute to a state of metaflammation that impacts immune cells and causes them to shift towards an immunosuppressive phenotype that, ultimately, allows tumor cells to evade immune control. Unfortunately, among the conventional therapeutic modalities and the novel therapeutic agents introduced, pancreatic cancer still holds one of the lowest response rates to therapy. Human antigen R (HuR), an RNA binding protein (RBP), has been repeatedly found to be implicated in pancreatic carcinogenesis and chemotherapy resistance through the posttranscriptional binding and regulation of mRNA target genes. Additionally, its overexpression has been linked to adverse clinical outcomes, in terms of tumor grade, stage, lymph node status and metastasis. These properties suggest the prospective role that HuR’s therapeutic targeting can play in facilitating pancreatic neoplasia and could provide the means to overcome chemoresistance.
Highlights
Pancreatic ductal adenocarcinoma (PDA) represents the fourth (4th) most common cause of cancer mortality in developed countries [1], with geographical variations and lifestyle factors shaping the context of its incidence
We focus on Human antigen R (HuR), an RNA-binding protein, and its therapeutic significance in pancreatic neoplasia and inflammation
DR5 expression and TRAIL sensitivity [55]. They further demonstrated that HuR translocates to the cytoplasm in response to sTRAIL treatment and that HuR has the ability to posttranscriptionally bind death receptor 4 (DR4) mRNA through the 30 -UTR. They utilized specific small interfering RNA (siRNA) to silence HuR in PDA cell lines in the presence of sTRAIL, which resulted in an increase in DR4 cell surface protein expression, suggesting that HuR plays a role in the downregulation of TRAIL-induced DR4 mRNA expression [55]
Summary
Pancreatic ductal adenocarcinoma (PDA) represents the fourth (4th) most common cause of cancer mortality in developed countries [1], with geographical variations and lifestyle factors shaping the context of its incidence. A large genomic analysis study performed by Bailey et al [7] in 2016 of 456 PDAs led to the identification of 32 recurrently mutated genes that resulted in classifying these tumors into four subtypes, each of them correlated with specific histopathologic characteristics. These subtypes include (a) squamous; (b) pancreatic progenitor; (c) immunogenic and (d) aberrantly differentiated endocrine exocrine (ADEX) [7]. We focus on HuR, an RNA-binding protein, and its therapeutic significance in pancreatic neoplasia and inflammation
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