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

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

doi:10.3389/fcell.2021.667551

Cited by 6 publications

(1 citation statement)

References 53 publications

(66 reference statements)

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“…Accumulated evidence reveals that Cirbp has been implicated in different physiological and pathological processes, including cell proliferation and differentiation, cell senescence, cell survival and apoptosis, oxidative stress, DNA damage and repair, immune and inflammatory responses, telomere maintenance, circadian rhythm, spermatogenesis, and tumor formation and progression, etc [ 4 , 10 , 35 , 59 , 61 , 73 , 137 , 138 ]. Furthermore, Cirbp functions as a tumor suppressor in ovarian carcinoma and endometrial carcinoma, whereas Cirbp exerts its pro-tumorigenic roles in pancreatic cancer, breast cancer, colorectal cancer, lung cancer, melanoma, prostate cancer, bladder cancer and skin squamous cell carcinoma [ 10 , 11 , 16 , 41 , 47 , 58 , 59 , 71 , 73 , 137 , 138 ], indicating that Cirbp has context-dependent tumor-suppressive and oncogenic functions in oncogenesis and cancer progression. Our previous study revealed that the significantly decreased expression of Cirbp was found in the clinical specimens of human nasopharyngeal carcinoma (NPC) [ 61 ].…”

Section: Introductionmentioning

confidence: 99%

ThermomiR-377-3p-induced suppression of Cirbp expression is required for effective elimination of cancer cells and cancer stem-like cells by hyperthermia

Lin,

Jia,

Luo

et al. 2024

J Exp Clin Cancer Res

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Background In recent years, the development of adjunctive therapeutic hyperthermia for cancer therapy has received considerable attention. However, the mechanisms underlying hyperthermia resistance are still poorly understood. In this study, we investigated the roles of cold‑inducible RNA binding protein (Cirbp) in regulating hyperthermia resistance and underlying mechanisms in nasopharyngeal carcinoma (NPC). Methods CCK-8 assay, colony formation assay, tumor sphere formation assay, qRT-PCR, Western blot were employed to examine the effects of hyperthermia (HT), HT + oridonin(Ori) or HT + radiotherapy (RT) on the proliferation and stemness of NPC cells. RNA sequencing was applied to gain differentially expressed genes upon hyperthermia. Gain-of-function and loss-of-function experiments were used to evaluate the effects of RNAi-mediated Cirbp silencing or Cirbp overexpression on the sensitivity or resistance of NPC cells and cancer stem-like cells to hyperthermia by CCK-8 assay, colony formation assay, tumorsphere formation assay and apoptosis assay, and in subcutaneous xenograft animal model. miRNA transient transfection and luciferase reporter assay were used to demonstrate that Cirbp is a direct target of miR-377-3p. The phosphorylation levels of key members in ATM-Chk2 and ATR-Chk1 pathways were detected by Western blot. Results Our results firstly revealed that hyperthermia significantly attenuated the stemness of NPC cells, while combination treatment of hyperthermia and oridonin dramatically increased the killing effect on NPC cells and cancer stem cell (CSC)‑like population. Moreover, hyperthermia substantially improved the sensitivity of radiation‑resistant NPC cells and CSC‑like cells to radiotherapy. Hyperthermia noticeably suppressed Cirbp expression in NPC cells and xenograft tumor tissues. Furthermore, Cirbp inhibition remarkably boosted anti‑tumor‑killing activity of hyperthermia against NPC cells and CSC‑like cells, whereas ectopic expression of Cirbp compromised tumor‑killing effect of hyperthermia on these cells, indicating that Cirbp overexpression induces hyperthermia resistance. ThermomiR-377-3p improved the sensitivity of NPC cells and CSC‑like cells to hyperthermia in vitro by directly suppressing Cirbp expression. More importantly, our results displayed the significantly boosted sensitization of tumor xenografts to hyperthermia by Cirbp silencing in vivo, but ectopic expression of Cirbp almost completely counteracted hyperthermia-mediated tumor cell-killing effect against tumor xenografts in vivo. Mechanistically, Cirbp silencing-induced inhibition of DNA damage repair by inactivating ATM-Chk2 and ATR-Chk1 pathways, decrease in stemness and increase in cell death contributed to hyperthermic sensitization; conversely, Cirbp overexpression-induced promotion of DNA damage repair, increase in stemness and decrease in cell apoptosis contributed to hyperthermia resistance. Conclusion Taken together, these findings reveal a previously unrecognized role for Cirbp in positively regulating hyperthermia resistance and suggest that thermomiR-377-3p and its target gene Cirbp represent promising targets for therapeutic hyperthermia.

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Section: Introductionmentioning

confidence: 99%

ThermomiR-377-3p-induced suppression of Cirbp expression is required for effective elimination of cancer cells and cancer stem-like cells by hyperthermia

Lin,

Jia,

Luo

et al. 2024

J Exp Clin Cancer Res

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Expression and prediction of genes related to IGF2BP3 in gastric cancer*

Yang

Sun

2022

Oncology and Translational Medicine

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ObjectiveGastric cancer (GC) is one of the most prevalent cancers worldwide and is associated with high morbidity and mortality rates. The IGF2 mRNA-binding protein (IGF2BP) participates in a variety of cancers. The aim of this study was to analyze the expression of IGF2BP3 and explore the genes related to IGF2BP3 in GC.MethodsBioinformatics software was used to analyze the expression of IGF2BP1, IGF2BP2, and IGF2BP3 in tumors, and the expression of IGF2BPs in the GSE118897 dataset. Immunohistochemistry was performed to detect the protein level of IGF2BP3 in GC samples. cBioPortal was used to query gene alteration of IGF2BP3. LinkedOmics was used to identify genes related to IGF2BP3.ResultsSangerbox analysis showed that the expression of all IGF2BP family members was higher in GC. cBioporta analysis showed that gene alteration of IGF2BP3 in stomach adenocarcinoma included mutation and amplificatio. LinkedOmics analysis showed that many genes were correlated with IGF2BP3, such as PLAGL2, GET4, IGF2BP1, HMGA2, CLDN6, HOXC13, SMARCA2, TMEM66, CIRBP, NFIX, SLC25A12, and CYB5D2.ConclusionIn this study, we founded that IGF2BP3 was overexpressed in GC. Furthermore, this study identified potential genes related to IGF2BP3 in GC, which should be studied further.

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GADD45β‐MTK1 signaling axis mediates oncogenic stress‐induced activation of the p38 and JNK pathways

Kawataki,

Kubota,

Katayama

et al. 2024

Cancer Science

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The ERK pathway governs essential biological processes such as cell proliferation and survival, and its hyperactivation by various oncogenes ultimately drives carcinogenesis. However, normal mammalian cells typically recognize aberrant ERK signaling as oncogenic stress and respond by inducing cell cycle arrest or apoptosis through activation of the p38 and JNK pathways. Despite the critical role of this response in preventing carcinogenesis, the precise molecular mechanisms underlying oncogene‐induced, ERK‐dependent activation of p38/JNK and its tumor‐suppressive effects remain unclear. Here, we demonstrate that MAP three kinase 1 (MTK1), a stress‐responsive MAPKKK, serves as a key mediator of p38/JNK activation induced by oncogenic ERK signaling. Mechanistically, aberrant ERK signaling induces sustained expression of the transcription factor early growth response protein 1 (EGR1), which promotes the production of the MTK1 activator GADD45β, leading to persistent activation of MTK1‐p38/JNK signaling. Gene knockout and transcriptome analyses revealed that this GADD45β/MTK1‐mediated cross‐talk between the ERK and p38/JNK pathways preferentially upregulates a specific set of genes involved in apoptosis and the immune response. Notably, the expression of EGR1, GADD45β, and MTK1 is frequently downregulated in many cancers with high ERK activity, resulting in the disruption of the tumor‐suppressive ERK‐p38/JNK cross‐talk. Restoring GADD45β expression in cancer cells reactivates p38/JNK signaling and suppresses tumorigenesis. Our findings delineate a molecular mechanism by which normal cells sense and respond to oncogenic stress to prevent abnormal growth, and highlight the significance of its dysregulation in cancer.

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

Cited by 6 publications

References 53 publications

ThermomiR-377-3p-induced suppression of Cirbp expression is required for effective elimination of cancer cells and cancer stem-like cells by hyperthermia

ThermomiR-377-3p-induced suppression of Cirbp expression is required for effective elimination of cancer cells and cancer stem-like cells by hyperthermia

Expression and prediction of genes related to IGF2BP3 in gastric cancer*

GADD45β‐MTK1 signaling axis mediates oncogenic stress‐induced activation of the p38 and JNK pathways

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