Top

Digestive Diseases and Sciences

Published in:

01-08-2021 | Colorectal Cancer | Original Article

MiR-325 Promotes Oxaliplatin-Induced Cytotoxicity Against Colorectal Cancer Through the HSPA12B/PI3K/AKT/Bcl-2 Pathway

Authors: Li Zhang, Heping Chen, Yueqiong Song, Qing Gu, Lu Zhang, Qin Xie, Jin Xu, Min Zhang

Published in: Digestive Diseases and Sciences | Issue 8/2021

Abstract

Background

Oxaliplatin is one of the most effective chemotherapeutic drugs used for the treatment of colorectal cancer (CRC). However, intervention that attenuates the resistance of oxaliplatin is still required in the treatment of CRC.

Aims

To investigate the role of miR-325 in changing the oxaliplatin sensitivity to CRC cells.

Methods

Expression of miR-325 in colorectal cancer tissues and cell lines was measured by using qRT-PCR analysis. Cytotoxicity of oxaliplatin to control or miR-325-overexpressed HT29 and SW480 cells was evaluated by CCK-8 assays. Luciferase reporter assay was used to confirm the regulation of miR-325 on HSPA12B. Flow cytometry was performed to detect the mitochondrial membrane potential and cell apoptosis.

Results

Expression of miR-325 was decreased in colorectal cancer tissues and cell lines. However, overexpression of miR-325 can decrease the 50% inhibiting concentration of oxaliplatin to colorectal cancer cell lines HT29 and SW480. Mechanically, we confirmed that miR-325 targeted HSPA12B in colorectal cancer. Therefore, overexpression of miR-325 inhibited the phosphorylation of PI3K and AKT and decreased the expression of Bcl-2 to promote the oxaliplatin-induced mitochondrial apoptosis in colorectal cancer.

Conclusions

MiR-325 sensitizes the colorectal cancer cells to oxaliplatin-induced cytotoxicity through the HSPA12B/PI3K/AKT/Bcl-2 pathway.

Fearon ER. Molecular genetics of colorectal cancer. Annu Rev Pathol. 2011;6:479–507. https://doi.org/10.1146/annurev-pathol-011110-130235.CrossRefPubMed

Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90. https://doi.org/10.3322/caac.20107.CrossRefPubMed

Markowitz SD, Bertagnolli MM. Molecular origins of cancer: molecular basis of colorectal cancer. N Engl J Med. 2009;361:2449–2460. https://doi.org/10.1056/NEJMra0804588.CrossRefPubMedPubMedCentral

TaChung Yu, Guo Fangfang, Yanan Yu, et al. Fusobacterium nucleatum Promotes chemoresistance to colorectal cancer by modulating autophagy. Cell. 2017;170:e16. https://doi.org/10.1016/j.cell.2017.07.008.CrossRef

Dahan L, Sadok A, Formento JL, et al. Modulation of cellular redox state underlies antagonism between oxaliplatin and cetuximab in human colorectal cancer cell lines. Br J Pharmacol. 2009;158:610–620. https://doi.org/10.1111/j.1476-5381.2009.00341.x.CrossRefPubMedPubMedCentral

Armstrong J, Dass CR. Doxorubicin action on mitochondria: relevance to osteosarcoma therapy? Curr Drug Targets. 2018;19:432–438. https://doi.org/10.2174/1389450116666150416115852.CrossRefPubMed

Reyna DE, Gavathiotis E. Liposomal permeabilization assay to study the functional interactions of the BCL-2 family. Methods Mol Biol. 2019;1877:111–119. https://doi.org/10.1007/978-1-4939-8861-7_7.CrossRefPubMedPubMedCentral

Meyerhardt JA, Mayer RJ. Systemic therapy for colorectal cancer. N Engl J Med. 2005;352:476–487. https://doi.org/10.1056/NEJMra040958.CrossRefPubMed

Zhou Yunfei, Wan Guohui, Spizzo Riccardo, et al. miR-203 induces oxaliplatin resistance in colorectal cancer cells by negatively regulating ATM kinase. Mol Oncol. 2014;8:83–92. https://doi.org/10.1016/j.molonc.2013.09.004.CrossRefPubMed

10.

Yang Xiao, Zhu Fan, Chaoran Yu, et al. N-myc downstream-regulated gene 1 promotes oxaliplatin-triggered apoptosis in colorectal cancer cells via enhancing the ubiquitination of Bcl-2. Oncotarget. 2017;8:47709–47724. https://doi.org/10.18632/oncotarget.17711.CrossRefPubMedPubMedCentral

11.

Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004;22:23–30. https://doi.org/10.1200/JCO.2004.09.046.CrossRefPubMed

12.

Liu Hui, Cheng Xin-Hua. MiR-29b reverses oxaliplatin-resistance in colorectal cancer by targeting SIRT1. Oncotarget. 2018;9:12304–12315. https://doi.org/10.18632/oncotarget.24380.CrossRefPubMedPubMedCentral

13.

Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–233. https://doi.org/10.1016/j.cell.2009.01.002.CrossRefPubMedPubMedCentral

14.

Gargalionis AN, Basdra EK. Insights in microRNAs biology. Curr Top Med Chem. 2013;13:1493–1502.CrossRef

15.

Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435:834–838. https://doi.org/10.1038/nature03702.CrossRefPubMed

16.

Cummins JM, He Y, Leary RJ, et al. The colorectal microRNAome. Proc Natl Acad Sci USA. 2006;103:3687–3692. https://doi.org/10.1073/pnas.0511155103.CrossRefPubMedPubMedCentral

17.

Bandres E, Cubedo E, Agirre X, et al. Identification by real-time PCR of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoral tissues. Mol Cancer. 2006;5:29. https://doi.org/10.1186/1476-4598-5-29.CrossRefPubMedPubMedCentral

18.

Cao F, Yin LX. miR-122 enhances sensitivity of hepatocellular carcinoma to oxaliplatin via inhibiting MDR1 by targeting Wnt/β-catenin pathway. Exp Mol Pathol. 2019;106:34–43. https://doi.org/10.1016/j.yexmp.2018.10.009.CrossRefPubMed

19.

Que KT, Zhou Y, You Y, et al. MicroRNA-31-5p regulates chemosensitivity by preventing the nuclear location of PARP1 in hepatocellular carcinoma. J Exp Clin Cancer Res. 2018;37:268. https://doi.org/10.1186/s13046-018-0930-0.CrossRefPubMedPubMedCentral

20.

Yan LH, Chen ZN, Li L, et al. miR-135a promotes gastric cancer progression and resistance to oxaliplatin. Oncotarget. 2016;7:70699–70714. https://doi.org/10.18632/oncotarget.12208.CrossRefPubMedPubMedCentral

21.

Lin T, Zhou S, Gao H, et al. MicroRNA-325 is a potential biomarker and tumor regulator in human bladder cancer. Technol Cancer Res Treat. 2018;17:1533033818790536. https://doi.org/10.1177/1533033818790536.CrossRefPubMedPubMedCentral

22.

Liu M, Qi Z, Liu B, et al. RY-2f, an isoflavone analog, overcomes cisplatin resistance to inhibit ovarian tumorigenesis via targeting the PI3K/AKT/mTOR signaling pathway. Oncotarget. 2015;6:25281–25294. https://doi.org/10.18632/oncotarget.4634.CrossRefPubMedPubMedCentral

23.

Liu B, Wang C, Chen P, et al. RACKI induces chemotherapy resistance in esophageal carcinoma by upregulating the PI3K/AKT pathway and Bcl-2 expression. Onco Targets Ther. 2018;11:211–220. https://doi.org/10.2147/OTT.S152818.CrossRefPubMedPubMedCentral

24.

Chen W, Liu X, Yuan S, et al. HSPA12B overexpression induces cisplatin resistance in non-small-cell lung cancer by regulating the PI3K/Akt/NF-κB signaling pathway. Oncol Lett. 2018;15:3883–3889. https://doi.org/10.3892/ol.2018.7800.CrossRefPubMedPubMedCentral

25.

Lin CF, Chen CL, Chang WT, et al. Bcl-2 rescues ceramide- and etoposide-induced mitochondrial apoptosis through blockage of caspase-2 activation. J Biol Chem. 2005;280:23758–23765. https://doi.org/10.1074/jbc.M412292200.CrossRefPubMed

26.

Brunelle JK, Letai A. Control of mitochondrial apoptosis by the Bcl-2 family. J Cell Sci. 2009;122:437–441. https://doi.org/10.1242/jcs.031682.CrossRefPubMedPubMedCentral

27.

Li N, Zhang Z, Jiang G, et al. Nobiletin sensitizes colorectal cancer cells to oxaliplatin by PI3K/Akt/MTOR pathway. Front Biosci (Landmark Ed). 2019;24:303–312.CrossRef

28.

Wang Q, Wei J, Wang C, et al. Gambogic acid reverses oxaliplatin resistance in colorectal cancer by increasing intracellular platinum levels. Oncol Lett. 2018;16:2366–2372. https://doi.org/10.3892/ol.2018.8916.CrossRefPubMedPubMedCentral

29.

Li H, Huang W, Luo R. The microRNA-325 inhibits hepatocellular carcinoma progression by targeting high mobility group box 1. Diagn Pathol. 2015;10:117. https://doi.org/10.1186/s13000-015-0323-z.CrossRefPubMedPubMedCentral

30.

Yao S, Zhao T, Jin H. Expression of MicroRNA-325-3p and its potential functions by targeting HMGB1 in non-small cell lung cancer. Biomed Pharmacother. 2015;70:72–79. https://doi.org/10.1016/j.biopha.2015.01.013.CrossRefPubMed

31.

Ma H, Lu T, Zhang X, et al. HSPA12B: a novel facilitator of lung tumor growth. Oncotarget. 2015;6:9924–9936. https://doi.org/10.18632/oncotarget.3533.CrossRefPubMedPubMedCentral

32.

Yren A, Yan G, You B, et al. Down-regulation of mammalian sterile 20-like kinase 1 by heat shock protein 70 mediates cisplatin resistance in prostate cancer cells. Cancer Res. 2008;68:2266–2274. https://doi.org/10.1158/0008-5472.can-07-6248.CrossRef

33.

Yoshidomi K, Murakami A, Yakabe K, et al. Heat shock protein 70 is involved in malignant behaviors and chemosensitivities to cisplatin in cervical squamous cell carcinoma cells. J Obstet Gynaecol Res. 2014;40:1188–1196. https://doi.org/10.1111/jog.12325.CrossRefPubMed

34.

Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501. https://doi.org/10.1038/nrc839.CrossRefPubMed

35.

Freudlsperger C, Burnett JR, Friedman JA, et al. EGFR-PI3K-AKT-mTOR signaling in head and neck squamous cell carcinomas: attractive targets for molecular-oriented therapy. Expert Opin Ther Targets. 2011;15:63–74. https://doi.org/10.1517/14728222.2011.541440.CrossRefPubMed

Title: MiR-325 Promotes Oxaliplatin-Induced Cytotoxicity Against Colorectal Cancer Through the HSPA12B/PI3K/AKT/Bcl-2 Pathway
Authors: Li Zhang
Heping Chen
Yueqiong Song
Qing Gu
Lu Zhang
Qin Xie
Jin Xu
Min Zhang
Publication date: 01-08-2021
Publisher: Springer US
Keywords: Colorectal Cancer
Colorectal Cancer
Published in: Digestive Diseases and Sciences / Issue 8/2021
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI: https://doi.org/10.1007/s10620-020-06579-7

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

MiR-325 Promotes Oxaliplatin-Induced Cytotoxicity Against Colorectal Cancer Through the HSPA12B/PI3K/AKT/Bcl-2 Pathway

Abstract

Background

Aims

Methods

Results

Conclusions

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Aims

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 8/2021

Clinical Outcomes of Acute Pancreatitis in Patients with Cirrhosis According to Liver Disease Severity Scores

Shortened-Interval Dual-Session EDGE Reduces the Risk of LAMS Dislodgement While Facilitating Timely ERCP

Exploring the Pathogenic Role and Therapeutic Implications of Interleukin 2 in Autoimmune Hepatitis

Comprehensive Analysis of Barrett’s Esophagus: Focused on Carcinogenic Potential for Barrett’s Cancer in Japanese Patients

Antibodies Against Glycoprotein 2 Are Specific Biomarkers for Pediatric Crohn’s Disease

Guidelines for the Perplexed: How to Maximize Colonoscopy Efficiency During the COVID-19 Pandemic

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page