<p>CircHIPK3 Promotes Gemcitabine (GEM) Resistance in Pancreatic Cancer Cells by Sponging miR-330-5p and Targets RASSF1</p>

Abstract

Background: Pancreatic cancer is one of the most common malignant diseases in the world. Gemcitabine chemotherapy remains the most important clinical treatment. However, research found that pancreatic cancer cells have chemoresistance to gemcitabine and the effect is not satisfactory. Therefore, it is urgent to find an effective early diagnosis and treatment strategy. Circular RNA is one of the most popular prognostic biomarkers in GEM-resistant PC. Materials and Methods: The present study was designed to evaluate the role of circHIPK3 in PC. The expression of circHIPK3 in PC tissues and cells and its effect on proliferation, migration, invasion, EMT, and apoptosis were investigated in vitro; its effect on tumor xenografts was assessed in vivo. Used bioinformation analysis to predict which miRNAs could potentially interact with circHIPK3, mRNA, and miR-330-5p. Results: RT-PCR showed that the level of circHIPK3 was increased in PC tumor tissues; moreover, circHIPK3 was also increased in GEM-resistant PC tumors tissues and GEMresistant PC cells. Sh-circHIPK3 could knockdown circHIPK3 in PANC-1-GEM and SW-1990-GEM and could significantly inhibit cell proliferation, invasion, migration, EMT and enhance cell apoptosis, compare with control group, the tumor xenografts of circHIPK3 knockdown group were significantly smaller. CircHIPK3 served as a sponge for miR-330-5p, and miR-330-5p directly bound to the 3′ UTR of RASSF1 were revealed by dual luciferase assay and RIP in PC cells. CircHIPK3 knockdown of RASSF1 expression could neutralize the cytological function of PC cells by miR-330-5p inhibitor mediated GEM-resistance. Conclusion: CircHIPK3 promotes gemcitabine (GEM) resistance in pancreatic cancer cells by targeting RASSF1 via miR-330-5p and regulates proliferation, invasive, migration, EMT, and apoptosis. Our research revealed that circHIPK3 may be a novel biomarker in GEMresistant PC and could be used as a prognostic target.

Current State of “Omics” Biomarkers in Pancreatic Cancer

“…Successfully accomplishing multi-omics data integration by systems biology approaches will fulfill future expectations and the need for robust, accurate, and feasible biomarker panels for pancreatic cancer. [166] Tumor tissue hsa_circ_0006215 Upregulated circRNA overexpression [167] Tumor tissue, plasma exosome circ-IARS Upregulated circRNA overexpression [168] Tumor tissue circ-PDE8A Upregulated circRNA overexpression [169] Tumor tissue/cell hsa_circ_0001649 Downregulated Microarray/qRT-PCR [170] Tumor tissue/cell hsa_circ_0005397 (circ-RHOT1) Upregulated Microarray/qRT-PCR [171] Tumor tissue/cell lines hsa_circ_0030235 Upregulated circRNA overexpression [172] Tumor tissue/cell lines hsa_circ_0007534 Upregulated circRNA overexpression [173] Tumor tissue/cell lines ciRS-7 (Cdr1as) Upregulated qRT-PCR [174] Tumor tissue hsa_circ_0007334 Upregulated Microarray/qRT-PCR [175] Tumor tissue circLDLRAD3 Upregulated circRNA knockdown [176] Tumor tissue/cell circASH2L Upregulated Microarray/qRT-PCR [177] Tumor tissue/cell lines circADAM9 Upregulated circRNA knockdown [178] Tumor tissue/cell hsa_circ_001653 Upregulated circRNA knockdown [179] Tumor tissue/cell circHIPK3 Upregulated circRNA knockdown [180] Tumor tissue/cell circFOXK2 Upregulated circRNA knockdown [181] Tumor tissue hsa_circ_0009065 (circBFAR) Upregulated circRNA overexpression [70] Tumor tissue hsa_circ_0086375 (circNFIB1) Downregulated circRNA knockdown [182] Tumor tissue/cell hsa_circ_0013912 Upregulated circRNA overexpression [183] Tumor tissue/cell lines hsa_circ_001587 Downregulated circRNA knockdown [184] Tumor [194] Tumor tissue BC008363 Upregulated Microarray/qRT-PCR [195] Tumor tissue HSATII Upregulated RNA-seq [196] Serum/plasma U2snRNA Upregulated Microarray/qRT-PCR [197] Pancreatic * CZE: capillary zone electrophoresis, ELISA: enzyme-linked immunosorbent assay, ELLA: Enzyme-linked lectin assay, FISH: fluorescence in situ hybridization, GC: gas chromatography, HILIC: Hydrophilic interaction chromatography, HRMAS: high-resolution magic angle spinning, LC: liquid chromatography, MS: mass spectrometry, NMR: nuclear magnetic resonance, qRT-PCR: quantitative reverse transcription polymerase chain reaction, TOF: time of flight, WB: Western blot, WES: Whole exome sequencing, WGS: whole genome ...…”

The Biological Role of Sponge Circular RNAs in Gastric Cancer: Main Players or Coadjuvants?

“…These circRNAs were also the most critical for other types of gastrointestinal tumors (Table S8). Surprisingly, circHIPK3 and circPVT1 have already been found to be dysregulated in hepatocellular carcinoma, colorectal and pancreatic cancers [9][10][11][12][13]. ciR-7 is another circRNA that is dysregulated in these four types of tumors [11].…”

“…They can also act as templates for protein translation and mediate immune responses [7,8]. Dysregulation in their role as miRNA-sponge has been reported in several types of gastrointestinal malignancies, including hepatocellular carcinoma [9][10][11], pancreatic [10,12], colorectal [10,11,13] and gastric cancer .…”

“…They can also act as templates for protein translation and mediate immune responses [ 7 , 8 ]. Dysregulation in their role as miRNA-sponge has been reported in several types of gastrointestinal malignancies, including hepatocellular carcinoma [ 9 , 10 , 11 ], pancreatic [ 10 , 12 ], colorectal [ 10 , 11 , 13 ] and gastric cancer [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ,…”

CircRNAs: biogenesis, functions, and role in drug-resistant Tumours

“…CircRNA_001275 is significantly upregulated in CDDP-resistant oesophageal cancer tissues and cells. Overexpression of circRNA_001275 promotes the proliferation and invasion of CDDP-resistant cells, reduces their apoptosis, and promotes CDDP resistance by upregulating Wnt7a expression by sponging miR-370-3p [ 153 ].…”