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MiR-92b-3p Regulates Cell Cycle and Apoptosis by Targeting CDKN1C, Thereby Affecting the Sensitivity of Colorectal Cancer Cells to Chemotherapeutic Drugs.

ABSTRACT: Colorectal cancer (CRC) is the third most common malignant tumor in the world and the second leading cause of cancer death. Multidrug resistance (MDR) has become a major obstacle in the clinical treatment of CRC. The clear molecular mechanism of MDR is complex, and miRNAs play an important role in drug resistance. This study used small RNAomic screens to analyze the expression profiles of miRNAs in CRC HCT8 cell line and its chemoresistant counterpart HCT8/T cell line. It was found that miR-92b-3p was highly expressed in HCT8/T cells. Knockdown of miR-92b-3p reversed the resistance of MDR HCT8/T cells to chemotherapeutic drugs in vitro and in vivo. Paclitaxel (PTX, a chemotherapy medication) could stimulate CRC cells to up-regulate miR-92b-3p expression and conferred cellular resistance to chemotherapeutic drugs. In studies on downstream molecules, results suggested that miR-92b-3p directly targeted Cyclin Dependent Kinase Inhibitor 1C (CDKN1C, which encodes a cell cycle inhibitor p57Kip2) to inhibit its expression and regulate the sensitivity of CRC cells to chemotherapeutic drugs. Mechanism study revealed that the miR-92b-3p/CDKN1C axis exerted a regulatory effect on the sensitivity of CRC cells via the regulation of cell cycle and apoptosis. In conclusion, these findings showed that miR-92b-3p/CDKN1C was an important regulator in the development of drug resistance in CRC cells, suggesting its potential application in drug resistance prediction and treatment.

SUBMITTER: Zhao F

PROVIDER: S-EPMC8268555 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe progression of all cancers is characterized by increased-cell proliferation and decreased-apoptosis. The androgen-independent prostate cancer (AIPC) is the terminal stage of the disease. Many chemokines and cytokines are suspects to cause this increased tumor cell survival that ultimately leads to resistance to therapy and demise of the host. The AIPC cells, but not androgen-responsive cells, constitutively express abundant amount of the pro-inflammatory chemokine, Interleukin-8 (IL-8). The mechanism of IL-8 mediated survival and therapeutic resistance in AIPC cells is unclear at present. The purpose of this report is to show the pervasive role of IL-8 in malignant progression of androgen-independent prostate cancer (AIPC) and to provide a potential new therapeutic avenue, using RNA interference.ResultsThe functional consequence of IL-8 depletion in AIPC cells was investigated by RNA interference in two IL-8 secreting AIPC cell lines, PC-3 and DU145. The non-IL-8 secreting LNCaP and LAPC-4 cells served as controls. Cells were transfected with RISC-free siRNA (control) or validated-pool of IL-8 siRNA. Transfection with 50 nM IL-8 siRNA caused >95% depletion of IL-8 mRNA and >92% decrease in IL-8 protein. This reduction in IL-8 led to cell cycle arrest at G1/S boundary and decreases in cell cycle-regulated proteins: Cyclin D1 and Cyclin B1 (both decreased >50%) and inhibition of ERK1/2 activity by >50%. Further, the spontaneous apoptosis was increased by >43% in IL-8 depleted cells, evidenced by increases in caspase-9 activation and cleaved-PARP. IL-8 depletion caused significant decreases in anti-apoptotic proteins, BCL-2, BCL-xL due to decrease in both mRNA and post-translational stability, and increased levels of pro-apoptotic BAX and BAD proteins. More significantly, depletion of intracellular IL-8 increased the cytotoxic activity of multiple chemotherapeutic drugs. Specifically, the cytotoxicity of Docetaxel, Staurosporine and Rapamycin increased significantly (>40% at IC50 dose) in IL-8 depleted cells as compared to that in C-siRNA transfected cells.ConclusionThese results show the pervasive role of IL-8 in promoting tumor cell survival, and resistance to cytotoxic drugs, regardless of the cytotoxic mechanism of antiproliferative drugs, and point to potential therapeutic significance of IL-8 depletion in men with AIPC.

Project description:BackgroundsPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer types and chemotherapeutic drug resistance is a stumbling block in improving the overall survival of PDAC patients. The nature of specific drug resistant subpopulation within pancreatic ductal adenocarcinoma is believed to be partly attributed to epithelial-mesenchymal transition (EMT) and cell stemness. Various PDAC cell lines show various degrees of resistance to chemotherapeutic agents including gemcitabine (GEM) and 5-fluorouracil (5-FU). In-depth understanding of drug resistance mechanisms and profile heterogeneities could lead to the development of novel and precise therapeutic strategies for addressing the chemo-resistant dilemma in PDAC patients.MethodsCytotoxicity assays were performed by CCK8 in ten common PDAC cell lines including AsPC-1, BxPC-3, CAPAN-1, CFPAC, HPAFII, MIA PaCa-2, PANC-1, Patu-8988, SW1990 and T3M4. RNA-seq data of the ten cell lines were downloaded from Cancer Cell Line Encyclopedia (CCLE) database and subsequently analyzed for differentially expressed genes (DEGs). Based on first-line chemotherapy regimens of PDAC, DEGs between resistant and sensitive cell lines were validated by qRT-PCR. Enriched pathways of differentially expressed genes between the resistant and sensitive cell lines were acquired by Metascape database.ResultsWe found that the top two toxic drugs for PDAC cell lines were paclitaxel (PTX) and GEM. Among the ten PDAC cell lines, SW1990 was the most resistant PDAC cell line with the highest IC50 levels for three drugs, while MIA PaCa-2 and BxPC-3 were the most sensitive PDAC cell lines. Differential expression analysis revealed the highest number of DEGs associated with cisplatin (CIS) sensitivity up to 642 genes, of which 181 genes were upregulated and 461 genes were downregulated in CIS-resistant cell lines. The least number of DEGs are associated with GEM sensitivity, of which 37 genes were highly expressed in GEM-resistant PDAC cell lines and 25 genes were lowly expressed. Enrichment analysis of the DEGs revealed that pathways associated with drug resistance were mainly extracellular matrix and cell-cell junction related pathways.ConclusionsPDAC cell lines showed diverse sensitivities to commonly used chemotherapeutic agents, which was caused by differential gene expression between the resistant and sensitive cell lines. The heterogeneity and its associated genes were enriched in extracellular matrix and cell-cell junction related pathways. Our study first portrayed the sensitivity profile to chemotherapeutic drugs of PDAC, which would benefit the chemoresistance mechanism study by reemphasizing the vital role of extracellular matrix and cell-cell junction related pathways and helping the selection of suitable PDAC cell lines.

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MiR-92b-3p Regulates Cell Cycle and Apoptosis by Targeting CDKN1C, Thereby Affecting the Sensitivity of Colorectal Cancer Cells to Chemotherapeutic Drugs.

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