CIRBP Knockdown Attenuates Tumourigenesis and Improves the Chemosensitivity of Pancreatic Cancer via the Downregulation of DYRK1B

Xiang Chen,Zhinan Zheng,Sanqing Jin,Xin Wang,Hongyu Xie

doi:10.3389/fcell.2021.667551

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies worldwide with very limited treatment options. Cold-inducible RNA binding protein (CIRBP) plays promoting roles in several types of cancers, but its function remains unclear in PDAC. Here, we found that the expression of CIRBP was upregulated in PDAC tumor tissues and was significantly associated with poor prognosis. Knockdown of CIRBP in PANC-1 and SW1990 cells inhibited proliferation, migration and invasion in vitro and suppressed tumor growth in vivo. Moreover, CIRBP knockdown enhanced the antitumour effects of gemcitabine treatment in PANC-1 and SW1990 cells, whereas CIRBP overexpression exerted the opposite effects. Mechanistically, CIRBP promoted PDAC malignancy and chemoresistance via upregulation of dual-specificity tyrosine-Y-phosphorylation regulated kinase 1B (DYRK1B). Indeed, knockdown of CIRBP sensitized pancreatic tumors to gemcitabine treatment by diminishing DYRK1B expression and increasing the ratio of ERK/p38 activity. Our findings suggest that CIRBP overexpression facilitates PDAC progression and gemcitabine resistance by upregulating DYRK1B expression and inhibiting the ERK/p38 signaling pathway, highlighting CIRBP as a potential new therapeutic target for PDAC.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and its 5-year survival rate is approximately 7–9% (Bray et al, 2018; Siegel et al, 2020)
As Cold-inducible RNA binding protein (CIRBP) exhibits a strong association with tumorigenesis in several types of cancers, we evaluated the expression levels of CIRBP in pancreatic cancer tissue microarrays containing 90 specimens of primary pancreatic cancer and 60 specimens of normal adjacent pancreatic tissue
Kaplan–Meier survival analysis showed that high CIRBP staining was strongly associated with poor Overall survival (OS) (P < 0.001, Figure 1E), with a median survival time of 10 months in the high CIRBP staining group compared to 38 months in the low CIRBP staining group

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and its 5-year survival rate is approximately 7–9% (Bray et al, 2018; Siegel et al, 2020). It is of vital importance to Knockdown CIRBP Inhibits Pancreatic Cancer explore the molecular mechanisms of carcinogenesis and chemosensitivity in PDAC to discover novel and more effective therapeutic approaches. Cold-inducible RNA binding protein (CIRBP), called DNA damage-induced transcript (A18 hnRNP), is a nuclear protein, but it tends to translocate to the cytoplasm in response to cellular stresses, such as cold, ultraviolet radiation, and hypoxia (Chappell et al, 2001; Yang and Carrier, 2001; Lujan et al, 2018). CIRBP was originally considered as a tumor suppressor that inhibits tumor cell proliferation by prolonging the G1 phase of the cell cycle and participating in the DNA damage response (Yang et al, 2006). High CIRBP expression in these tumors results in low chemosensitivity and poor prognosis (Zeng et al, 2009; Zhu et al, 2016; Zhou et al, 2018)

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