Inhibition of miR-182-5p protects cardiomyocytes from hypoxia-induced apoptosis by targeting CIAPIN1

2018 ◽  
Vol 96 (5) ◽  
pp. 646-654 ◽  
Author(s):  
Yunsong Zhang ◽  
Jun Fang ◽  
Huiwen Ma
Keyword(s):  
Molecular Mechanisms ◽  
Annexin V ◽  
Bioinformatic Analysis ◽  
Luciferase Reporter ◽  
Protective Effects ◽  
Small Interfering Rnas ◽  
Protein Levels ◽  
Hypoxic Conditions ◽  
Induced Apoptosis ◽  
Apoptosis Inhibitor

Myocardial infarction (MI), a type of ischemic heart disease, is generally accompanied by apoptosis of cardiomyocytes. MicroRNAs play the vital roles in the development and physiology of MI. Here, we established a downregulation model of miR-182-5p in H9c2 cells under hypoxic conditions to investigate the potential molecular mechanisms for miR-182-5p in hypoxia-induced cardiomyocyte apoptosis (HICA). RT-qPCR indicated that miR-182-5p levels exhibit a time-dependent increase in the rate of apoptosis induced by hypoxia. The results from the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and LDH (lactate dehydrogenase) assays indicated that cardiomyocyte injury noticeably increased after exposure to hypoxia. Meanwhile, hypoxia dramatically increased the apoptosis rate [which was reflected in the results from the annexin V – propidium iodide (PI) assay], enhanced caspase-3 activity, and reduced the expression of Bcl-2. Downregulation of miR-182-5p can significantly reverse hypoxia-induced cardiomyocyte injury or apoptosis. Importantly, bioinformatic analysis and dual-luciferase reporter assay revealed that CIAPIN1 (cytokine-induced apoptosis inhibitor 1) was a direct functional target of miR-182-5p, and that inhibition of miR-182-5p can lead to an increase in CIAPIN1 expression at both the mRNA and protein levels. Furthermore, the knockdown of CIAPIN1 with small interfering RNAs (siRNAs) efficiently abolished the protective effects of miR-182-5p inhibitor on HICA, demonstrating that miR-182-5p plays a pro-apoptotic role in cardiomyocytes under hypoxic conditions by downregulating CIAPIN1. Collectively, our results demonstrate that miR-182-5p may serve an underlying target to prevent cardiomyocytes from hypoxia-induced injury or apoptosis.

scholarly journals Grape Seed Procyanidin B2 Protects Porcine Ovarian Granulosa Cells against Oxidative Stress-Induced Apoptosis by Upregulating let-7a Expression

2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Jia-Qing Zhang ◽  
Xian-Wei Wang ◽  
Jun-Feng Chen ◽  
Qiao-Ling Ren ◽  
Jing Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Critical Role ◽  
Grape Seed ◽  
Luciferase Reporter ◽  
Tunel Staining ◽  
Protective Effects ◽  
Beneficial Effects ◽  
Protein Levels ◽  
Underlying Mechanisms ◽  
Induced Apoptosis

Oxidative stress is a causal factor and key promoter of all kinds of reproductive disorders related to granulosa cell (GC) apoptosis that acts by dysregulating the expression of related genes. Various studies have suggested that grape seed procyanidin B2 (GSPB2) may protect GCs from oxidative injury, though the underlying mechanisms are not fully understood. Therefore, whether the beneficial effects of GSPB2 are associated with microRNAs, which have been suggested to play a critical role in GC apoptosis by regulating the expression of protein-coding genes, was investigated in this study. The results showed that GSPB2 treatment protected GCs from a H2O2-induced apoptosis, as detected by an MTT assay and TUNEL staining, and increased let-7a expression in GCs. Furthermore, let-7a overexpression markedly increased cell viability and inhibited H2O2-induced GC apoptosis. Furthermore, the overexpression of let-7a reduced the upregulation of Fas expression in H2O2-treated GCs at the mRNA and protein levels. Dual-luciferase reporter assay results indicated that let-7a directly targets the Fas 3′-UTR. Furthermore, the overexpression of let-7a enhanced the protective effects of GSPB2 against GC apoptosis induced by H2O2. These results indicate that GSPB2 inhibits H2O2-induced apoptosis of GCs, possibly through the upregulation of let-7a.

scholarly journals Sheng Mai San protects H9C2 cells against hyperglycemia-induced apoptosis

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Bing Pang ◽  
Li-Wei Shi ◽  
Li-juan Du ◽  
Yun-Chu Li ◽  
Mei-Zhen Zhang ◽  
...  
Keyword(s):  
Cell Viability ◽  
Molecular Mechanisms ◽  
Annexin V ◽  
Signalling Pathway ◽  
H9c2 Cell ◽  
Protective Effects ◽  
H9c2 Cells ◽  
P53 Expression ◽  
Fasl Gene ◽  
Induced Apoptosis

Abstract Background Sheng Mai San (SMS) has been proven to exhibit cardio-protective effects. This study aimed to explore the molecular mechanisms of SMS on hyperglycaemia (HG)-induced apoptosis in H9C2 cells. Methods HG-induced H9C2 cells were established as the experimental model, and then treated with SMS at 25, 50, and 100 μg/mL. H9C2 cell viability and apoptosis were quantified using MTT and Annexin V-FITC assays, respectively. Furthermore, Bcl-2/Bax signalling pathway protein expression and Fas and FasL gene expression levels were quantified using western blotting and RT-PCR, respectively. Results SMS treatments at 25, 50, 100 μg/mL significantly improved H9C2 cell viability and inhibited H9C2 cell apoptosis (p < 0.05). Compared to the HG group, SMS treatment at 25, 50, and 100 μg/mL significantly downregulated p53 and Bax expression and upregulated Bcl-2 expression (p < 0.05). Moreover, SMS treatment at 100 μg/mL significantly downregulated Fas and FasL expression level (p < 0.05) when compared to the HG group. Conclusion SMS protects H9C2 cells from HG-induced apoptosis probably by downregulating p53 expression and upregulating the Bcl-2/Bax ratio. It may also be associated with the inhibition of the Fas/FasL signalling pathway.

The T(4;11) Fusion Protein MLL/AF4 Regulates TERT Expression

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3111-3111
Author(s):  
Andreas Gessner ◽  
Maria Thomas ◽  
Patricia Garrido Castro ◽  
Olaf Heidenreich ◽  
Johann Greil
Keyword(s):  
Cell Lines ◽  
Molecular Mechanisms ◽  
Fusion Transcript ◽  
Telomerase Activity ◽  
Small Interfering Rnas ◽  
Inhibition Of Proliferation ◽  
Knock Down ◽  
Protein Levels ◽  
Induced Apoptosis ◽  
Tert Expression

Abstract About 50% of all infants suffering from acute lymphoblastic leukaemia (ALL) show the translocation t(4;11)(q21;q23) which creates the fusion genes MLL/AF4 and AF4/MLL. This reciprocal translocation identifies a therapy resistant form of leukaemia with a poor prognosis. In order to gain a better insight into the molecular mechanisms of t(4;11) leukaemias we used the two ALL cell lines SEM and RS4;11, both harbouring the t(4;11) translocation, however with different fusion sites. Specific small interfering RNAs (siRNAs) against the two fusion site variants of the MLL/AF4 fusion transcript were designed and transfected into the respective cells via electroporation, using very mild conditions. Serial electroporations at two-day intervals resulted in sustained depletion of the MLL/AF4 transcript up to 70–80%, and depending on the experimental setup, cells were analysed after two or three electroporations. Knock-down of MLL/AF4 resulted in strong inhibition of proliferation and clonogenicity in the two t(4;11)-positive cell lines SEM and RS4;11, along with induction of apoptosis. MLL/AF4 depletion resulted in a 65% decrease in telomerase activity in both SEM and RS4;11 cells, with telomerase reverse transcriptase (TERT) expression being reduced twofold on both transcript and protein levels. Notably, TERT reduction was even stronger (90% depletion) when apoptosis caused by MLL/AF4 knock-down was suppressed with the caspase inhibitor zVAD. In contrast, levels of the RNA component of the telomerase, TERC, were not affected by MLL/AF4 knock-down. Additionally, MLL/AF4 knock-down was associated with reduced expression of several members of the HOXA gene cluster, HOXA6 (65% reduction), HOXA7 (85% reduction), HOXA9 (60% reduction) and HOXA10 (75% reduction). Interestingly, siRNA-mediated knock-down of the MLL/AF4 target gene HOXA7 also induced apoptosis and resulted in a 70% decrease of TERT levels in two t(4;11) positive cell lines without affecting MLL/AF4. Chromatin immunoprecipitation assays revealed HOXA7 binding to the promoter of TERT. Therefore, MLL/AF4 regulates TERT expression, at least in part, via HOXA7. These data suggest that t(4;11) positive cells with substantially lower TERT expression undergo apoptosis, and that TERT may play an antiapoptotic role in t(4;11) positive ALL. Furthermore, these studies identify TERT as a putative new therapeutic target in this therapy-resistant infant leukaemia.

Role of NF-κB in the Rescue of Multiple Myeloma Cells From Glucocorticoid-Induced Apoptosis by Bcl-2

Blood ◽  
1999 ◽  
Vol 93 (9) ◽  
pp. 3044-3052 ◽  
Author(s):  
Rena Feinman ◽  
Jadd Koury ◽  
Michael Thames ◽  
Bart Barlogie ◽  
Joshua Epstein ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dna Binding ◽  
Molecular Mechanisms ◽  
Annexin V ◽  
Early Event ◽  
Protective Effects ◽  
Mobility Shift ◽  
Myeloma Cells ◽  
Mobility Shift Assay ◽  
Induced Apoptosis

Abstract The molecular mechanisms by which multiple myeloma (MM) cells evade glucocorticoid-induced apoptosis have not been delineated. Using a human IgAκ MM cell line (ARP-1), we found that dexamethasone (Dex)-induced apoptosis is associated with decreased NF-κB DNA binding and κB-dependent transcription. Both nuclear p50:p50 and p50:p65 NF-κB complexes are detected in ARP-1 cells by supershift electrophoretic mobility shift assay (EMSA). Dex-mediated inhibition of NF-κB DNA binding precedes a notable increase in annexin V binding, thereby indicating that diminished NF-κB activity is an early event in Dex-induced apoptosis. Overexpression of bcl-2 in ARP-1 cells prevents Dex-mediated repression of NF-κB activity and apoptosis. Sustained NF-κB DNA binding is also observed in two previously characterized Dex-resistant MM cell lines (RPMI8226 and ARH-77) that express moderate levels of endogenous bcl-2 and IκB proteins. In addition, enforced bcl-2 expression in ARP-1 cells did not prevent the augmentation of IκB protein by Dex. We also noted a possible association between Dex-mediated downregulation of NF-κB in freshly obtained primary myeloma cells and the patients’ responsiveness to glucocorticoid-based chemotherapy. Collectively, our data suggest that the protective effects of bcl-2 in MM cells act upstream in the NF-κB activation–signaling pathway and the potential use of NF-κB as a biomarker in progressive MM.

Role of NF-κB in the Rescue of Multiple Myeloma Cells From Glucocorticoid-Induced Apoptosis by Bcl-2

Blood ◽  
1999 ◽  
Vol 93 (9) ◽  
pp. 3044-3052 ◽  
Author(s):  
Rena Feinman ◽  
Jadd Koury ◽  
Michael Thames ◽  
Bart Barlogie ◽  
Joshua Epstein ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dna Binding ◽  
Molecular Mechanisms ◽  
Annexin V ◽  
Early Event ◽  
Protective Effects ◽  
Mobility Shift ◽  
Myeloma Cells ◽  
Mobility Shift Assay ◽  
Induced Apoptosis

The molecular mechanisms by which multiple myeloma (MM) cells evade glucocorticoid-induced apoptosis have not been delineated. Using a human IgAκ MM cell line (ARP-1), we found that dexamethasone (Dex)-induced apoptosis is associated with decreased NF-κB DNA binding and κB-dependent transcription. Both nuclear p50:p50 and p50:p65 NF-κB complexes are detected in ARP-1 cells by supershift electrophoretic mobility shift assay (EMSA). Dex-mediated inhibition of NF-κB DNA binding precedes a notable increase in annexin V binding, thereby indicating that diminished NF-κB activity is an early event in Dex-induced apoptosis. Overexpression of bcl-2 in ARP-1 cells prevents Dex-mediated repression of NF-κB activity and apoptosis. Sustained NF-κB DNA binding is also observed in two previously characterized Dex-resistant MM cell lines (RPMI8226 and ARH-77) that express moderate levels of endogenous bcl-2 and IκB proteins. In addition, enforced bcl-2 expression in ARP-1 cells did not prevent the augmentation of IκB protein by Dex. We also noted a possible association between Dex-mediated downregulation of NF-κB in freshly obtained primary myeloma cells and the patients’ responsiveness to glucocorticoid-based chemotherapy. Collectively, our data suggest that the protective effects of bcl-2 in MM cells act upstream in the NF-κB activation–signaling pathway and the potential use of NF-κB as a biomarker in progressive MM.

scholarly journals MiR-489-3p inhibits cell proliferation, migration, and invasion, and induces apoptosis, by targeting the BDNF-mediated PI3K/AKT pathway in glioblastoma

2020 ◽  
Vol 15 (1) ◽  
pp. 274-283
Author(s):  
Bo Zheng ◽  
Tao Chen
Keyword(s):  
Cell Proliferation ◽  
Luciferase Reporter ◽  
Akt Pathway ◽  
Migration And Invasion ◽  
Bdnf Mrna ◽  
Protein Levels ◽  
Rna Immunoprecipitation ◽  
Underlying Mechanisms ◽  
Induced Apoptosis ◽  
Protein Cell

AbstractAmong astrocyte tumors, glioblastoma (GBM) is the most malignant glioma, highly aggressive and invasive, with extremely poor prognosis. Previous research has reported that microRNAs (miRNAs) participate in the progression of many cancers. Thus, this study aimed to explore the role and the underlying mechanisms of microRNA (miR)-489-3p in GBM progression. The expression of miR-489-3p and brain-derived neurotrophic factor (BDNF) mRNA was measured by quantitative real-time polymerase chain reaction. Western blot analysis was used to detect BDNF protein and the PI3K/AKT pathway-related protein. Cell proliferation, apoptosis, migration, and invasion were analyzed using CKK-8 assay, flow cytometry, and transwell assay, respectively. The interaction between BDNF and miR-489-3p was explored by luciferase reporter assay and RNA immunoprecipitation (RIP) assay. MiR-489-3p was down-regulated and BDNF was up-regulated in GBM tissues and cells. MiR-489-3p re-expression or BDNF knockdown inhibited GBM cell proliferation, migration, and invasion, and promoted apoptosis. BDNF was a target of miR-489-3p, and BDNF up-regulation reversed the effects of miR-489-3p on GBM cells. The protein levels of p-AKT and p-PI3K were notably reduced in GBM cells by overexpression of miR-489-3p, but were rescued following BDNF up-regulation. Therefore, miR-489-3p inhibited proliferation, migration, and invasion, and induced apoptosis, by targeting the BDNF-mediated PI3K/AKT pathway in GBM, providing new strategies for clinical treatment of GBM.

scholarly journals LINC00942 Promotes Tumor Proliferation and Metastasis in Lung Adenocarcinoma via FZD1 Upregulation

2021 ◽  
Vol 20 ◽  
pp. 153303382097752
Author(s):  
Ronghua Wang ◽  
Xiuyun Wang ◽  
Jingtao Zhang ◽  
Yanpei Liu
Keyword(s):  
Lung Adenocarcinoma ◽  
Wnt Signaling ◽  
Molecular Mechanisms ◽  
Bioinformatic Analysis ◽  
Luciferase Reporter ◽  
Regulatory Relationship ◽  
Potential Biomarker ◽  
Proliferation And Metastasis ◽  
Tumor Proliferation And Metastasis ◽  
Dual Luciferase Reporter Assay

Background: Long non-coding RNAs (lncRNAs) have been reported to play important roles in the progression of human cancers. Herein, bioinformatic analysis identified that LINC00942 was a highly overexpressed lncRNA in lung adenocarcinoma (LUAD). The present study aimed to explore the roles and possible molecular mechanisms of LINC00942 in LUAD. Methods: First, on the basis of TCGA database, the expression and prognosis of LINC00942 were analyzed in LUAD tissues. Then, si-LINC00942 was transfected into A549 and H1299 cells to knockdown the expression of LINC00942. Cell viability was detected by MTT assay. Flow cytometry was used to analyze cell apoptosis. The expressions of PCNA, Bax, Bcl-2, and wnt/β-catenin pathway proteins were detected by western blotting. Dual-luciferase reporter assay was used to evaluate the regulatory relationship between LINC00942 and miR-5006-5p, or miR-5006-5p and FZD1. Results: We discovered that LINC00942 was up-regulated in LUAD tissues compared with adjacent tissues. Besides, we found the increased LINC00942 expression was associated with poor survival. In addition, silencing of LINC00942 suppressed the proliferation, migration, invasion and facilitated the apoptosis of A549 and H1299 cells. Moreover, silencing of LINC00942 repressed the expression of PCNA, Bcl-2, and enhanced Bax expression in A549 and H1299 cells. Mechanically, LINC00942 exerted its effects via enhancing Wnt signaling. LINC00942 functioned as competing endogenous RNA (ceRNA) by binding to miR-5006-5p, upregulating the expression of FZD1, which was a direct target of miR-5006-5p. Conclusion: Our findings indicated that LINC00942/miR-5006-5p/FZD1 axis played important roles in LUAD growth through enhancing Wnt signaling. LINC00942/miR-5006-5p/FZD1 axis might serve as a potential biomarker and therapeutic target for LUAD treatment.

scholarly journals Circular RNA circCSPP1 knockdown attenuates doxorubicin resistance and suppresses tumor progression of colorectal cancer via miR-944/FZD7 axis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Lanlan Xi ◽  
Quanlin Liu ◽  
Wei Zhang ◽  
Linshan Luo ◽  
Jingfeng Song ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Growth ◽  
Circular Rna ◽  
Luciferase Reporter ◽  
Circular Rnas ◽  
Protein Levels ◽  
Cell Progression ◽  
Rna Immunoprecipitation ◽  
Induced Apoptosis

Abstract Background Circular RNAs (circRNAs) have been reported to play vital roles in colorectal cancer (CRC). However, only a few circRNAs have been experimentally validated and functionally described. In this research, we aimed to reveal the functional mechanism of circCSPP1 in CRC. Methods 36 DOX sensitive and 36 resistant CRC cases participated in this study. The expression of circCSPP1, miR-944 and FZD7 were detected by quantitative real time polymerase chain reaction (qRT-PCR) and the protein levels of FZD7, MRP1, P-gp and LRP were detected by western blot. Cell proliferation, migration, invasion, and apoptosis were assessed by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay, transwell assay, or flow cytometry analysis, respectively. The interaction between miR-944 and circCSPP1 or frizzled-7 (FZD7) was predicted by Starbase 3.0 and verified by the dual luciferase reporter assay, RNA immunoprecipitation (RIP) assay and RNA pull down assay. Xenograft tumor assay was performed to examine the effect of circCSPP1 on tumor growth in vivo. Results The expression of circCSPP1 and FZD7 was upregulated while miR-944 expression was downregulated in doxorubicin (DOX)-resistant CRC tissues and cells. CircCSPP1 knockdown significantly downregulated enhanced doxorubicin sensitivity, suppressed proliferation, migration, invasion, and induced apoptosis in DOX-resistant CRC cells. Interestingly, we found that circCSPP1 directly downregulated miR-944 expression and miR-944 decreased FZD7 level through targeting to 3′ untranslated region (UTR) of FZD7. Furthermore, circCSPP1 mediated DOX-resistant CRC cell progression and doxorubicin sensitivity by regulating miR-944/FZD7 axis. Besides, circCSPP1 downregulation dramatically repressed CRC tumor growth in vivo. Conclusion Our data indicated that circCSPP1 knockdown inhibited DOX-resistant CRC cell growth and enhanced doxorubicin sensitivity by miR-944/FZD7 axis, providing a potential target for CRC therapy.

scholarly journals Isorhynchophylline Protects PC12 Cells Against Beta-Amyloid-Induced Apoptosis via PI3K/Akt Signaling Pathway

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Yan-Fang Xian ◽  
Zhi-Xiu Lin ◽  
Qing-Qiu Mao ◽  
Jian-Nan Chen ◽  
Zi-Ren Su ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Pc12 Cells ◽  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Neuroprotective Effect ◽  
Protective Action ◽  
Protective Effects ◽  
Phosphorylated Akt ◽  
Induced Apoptosis

The neurotoxicity of amyloid-β(Aβ) has been implicated as a critical cause of Alzheimer’s disease. Isorhynchophylline (IRN), an oxindole alkaloid isolated fromUncaria rhynchophylla,exerts neuroprotective effect againstAβ25–35-induced neurotoxicityin vitro. However, the exact mechanism for its neuroprotective effect is not well understood. The present study aimed to investigate the molecular mechanisms underlying the protective action of IRN againstAβ25–35-induced neurotoxicity in cultured rat pheochromocytoma (PC12) cells. Pretreatment with IRN significantly increased the cell viability, inhibited the release of lactate dehydrogenase and the extent of DNA fragmentation inAβ25–35-treated cells. IRN treatment was able to enhance the protein levels of phosphorylated Akt (p-Akt) and glycogen synthase kinase-3β(p-GSK-3β). Lithium chloride blockedAβ25–35-induced cellular apoptosis in a similar manner as IRN, suggesting that GSK-3βinhibition was involved in neuroprotective action of IRN. Pretreatment with LY294002 completely abolished the protective effects of IRN. Furthermore, IRN reversedAβ25–35-induced attenuation in the level of phosphorylated cyclic AMP response element binding protein (p-CREB) and the effect of IRN could be blocked by the PI3K inhibitor. These experimental findings unambiguously suggested that the protective effect of IRN againstAβ25–35-induced apoptosis in PC12 cells was associated with the enhancement of p-CREB expression via PI3K/Akt/GSK-3βsignaling pathway.

scholarly journals Knockdown of Long Non-Coding RNA XIST Inhibited Doxorubicin Resistance in Colorectal Cancer by Upregulation of miR-124 and Downregulation of SGK1

2018 ◽  
Vol 51 (1) ◽  
pp. 113-128 ◽  
Author(s):  
Jia Zhu ◽  
Rui Zhang ◽  
Dongxiang Yang ◽  
Jibin Li ◽  
Xiaofei Yan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Western Blot ◽  
Molecular Mechanisms ◽  
Luciferase Reporter ◽  
Regulatory Function ◽  
Glutathione S Transferase ◽  
Protein Levels ◽  
Qrt Pcr ◽  
Ic50 Value

Background/Aims: Doxorubicin (DOX) is a widely used chemotherapeutic agent for colorectal cancer (CRC). However, the acquirement of DOX resistance limits its clinical application for cancer therapy. Mounting evidence has suggested that aberrantly expressed lncRNAs contribute to drug resistance of various tumors. Our study aimed to explore the role and molecular mechanisms of lncRNA X-inactive specific transcript (XIST) in chemoresistance of CRC to DOX. Methods: The expressions of XIST, miR-124, serum and glucocorticoid-inducible kinase 1 (SGK1) mRNA in DOX-resistant CRC tissues and cells were detected by qRT-PCR or western blot analysis. DOX sensitivity was assessed by detecting IC50 value of DOX, the protein levels of P-glycoprotein (P-gp) and glutathione S-transferase-π (GST-π) and apoptosis. The interactions between XIST, miR-124 and SGK1 were confirmed by luciferase reporter assay, qRT-PCR and western blot. Xenograft tumor assay was used to verify the role of XIST in DOX resistance in CRC in vivo. Results: XIST expression was upregulated and miR-124 expression was downregulated in DOX-resistant CRC tissues and cells. Knockdown of XIST inhibited DOX resistance of CRC cells, as evidenced by the reduced IC50 value of DOX, decreased P-gp and GST-π levels and enhanced apoptosis in XIST-silenced DOX-resistant CRC cells. Additionally, XIST positively regulated SGK1 expression by interacting with miR-124 in DOX-resistant CRC cells. miR-124 suppression strikingly reversed XIST-knockdown-mediated repression on DOX resistance in DOX-resistant CRC cells. Moreover, SGK1-depletion-elicited decrease of DOX resistance was greatly restored by XIST overexpression or miR-124 inhibition in DOX-resistant CRC cells. Furthermore, XIST knockdown enhanced the anti-tumor effect of DOX in CRC in vivo. Conclusion: XIST exerted regulatory function in resistance of DOX possibly through miR-124/SGK1 axis, shedding new light on developing promising therapeutic strategy to overcome chemoresistance in CRC patients.

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