Abstract
Cervical cancer (CC) is a common gynecological malignancy, accounting for 10% of all gynecological cancers. Recently, targeted therapy for CC has shown unprecedented advantages. To improve CC patients’ prognosis, there are still urgent needs to develop more promising therapeutic targets. Aldo-keto reductase 1 family member C1 (AKR1C1) is a type of aldosterone reductase and plays a regulatory role in a variety of key metabolic pathways. Several studies indicated that AKR1C1 was highly expressed in a series of tumors, and participated in the progression of these tumors. However, the possible effects of AKR1C1 on CC progression remain unclear. Herein, we revealed AKR1C1 was highly expressed in human CC tissues and correlated with the clinical characteristics of patients with CC. AKR1C1 could regulate the proliferation and invasion of cervical cancer cells in vitro. Further experiments showed that AKR1C1 could regulate TWIST1 expression and AKT pathway. In summary, we confirmed the involvement of AKR1C1 in CC progression, and therefore AKR1C1 may have the potential to be a molecular target for CC treatment.
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References
Abdel Raouf SM, Ibrahim TR, Abdelaziz LA, Farid MI, Mohamed SY (2019) Prognostic value of TWIST1 and EZH2 expression. Colon Cancer J Gastrointest Cancer. https://doi.org/10.1007/s12029-019-00344-4
Ardalan Khales S, Abbaszadegan MR, Majd A, Forghanifard MM (2019) Linkage between EMT and stemness state through molecular association between TWIST1 and NY-ESO1 in esophageal squamous cell carcinoma. Biochimie 163:84–93. https://doi.org/10.1016/j.biochi.2019.05.016
Brozic P, Smuc T, Gobec S, Rizner TL (2006) Phytoestrogens as inhibitors of the human progesterone metabolizing enzyme AKR1C1. Mol Cell Endocrinol 259:30–42. https://doi.org/10.1016/j.mce.2006.08.001
Cao W, Xu C, Li X, Yang X (2019) Twist1 promotes astrocytoma development by stimulating vasculogenic mimicry. Oncol Lett 18:846–855. https://doi.org/10.3892/ol.2019.10380
Chang WM, Chang YC, Yang YC, Lin SK, Chang PM, Hsiao M (2019) AKR1C1 controls cisplatin-resistance in head and neck squamous cell carcinoma through cross-talk with the STAT1/3 signaling pathway. J Exp Clin Cancer Res 38:245. https://doi.org/10.1186/s13046-019-1256-2
Chen JL et al (2020a) Extended-field bone marrow sparing radiotherapy for primary chemoradiotherapy in cervical cancer patients with para-aortic lymphadenopathy: volumetric-modulated arc therapy versus helical tomotherapy. J X-ray Sci Technol. https://doi.org/10.3233/XST-190593
Chen R et al (2020b) FGFRL1 affects chemoresistance of small-cell lung cancer by modulating the PI3K/Akt pathway via ENO1. J Cell Mol Med. https://doi.org/10.1111/jcmm.14763
Cui Z, Han B, Wang X, Li Z, Wang J, Lv Y (2019) Long non-coding RNA TTN-AS1 promotes the proliferation and invasion of colorectal cancer cells by activating miR-497-mediated PI3K/Akt/mTOR. Signal OncoTargets Therapy 12:11531–11539. https://doi.org/10.2147/ott.s229104
de Juan A et al (2020) SEOM clinical guidelines for cervical cancer (2019). Clin Transl Oncol. https://doi.org/10.1007/s12094-019-02271-z
Gao Y, Ma C, Feng X, Haimiti X, Liu Y (2020) BF12, a novel benzofuran, exhibits anti-tumor activity by inhibiting microtubules and the PI3K/Akt/mTOR signaling pathway in human cervical cancer cells. Chem Biodivers. https://doi.org/10.1002/cbdv.201900622
Gu Y, Wan C, Qiu J, Cui Y, Jiang T, Zhuang Z (2020) Circulating HPV cDNA in the blood as a reliable biomarker for cervical cancer: a meta-analysis. PloS ONE 15:e0224001. https://doi.org/10.1371/journal.pone.0224001
Guo W, Sun C, Jiang G, Xin Y (2019) Recent developments of nanoparticles in the treatment of photodynamic therapy for cervical cancer. Anti-cancer Agents Med Chem. https://doi.org/10.2174/1871520619666190411121953
Hamalainen L, Soini Y, Pasonen-Seppanen S, Siponen M (2019) Alterations in the expression of EMT-related proteins claudin-1, claudin-4 and claudin-7, E-cadherin, TWIST1 and ZEB1 in oral lichen planus. J Oral Pathol Med 48:735–744. https://doi.org/10.1111/jop.12917
Hevir N, Vouk K, Sinkovec J, Ribic-Pucelj M, Rizner TL (2011) Aldo-keto reductases AKR1C1, AKR1C2 and AKR1C3 may enhance progesterone metabolism in ovarian endometriosis. Chem Biol Interactions 191:217–226. https://doi.org/10.1016/j.cbi.2011.01.003
Huebbers CU et al (2019) Upregulation of AKR1C1 and AKR1C3 expression in OPSCC with integrated HPV16 and HPV-negative tumors is an indicator of poor prognosis. Int J Cancer 144:2465–2477. https://doi.org/10.1002/ijc.31954
Ji Q et al (2004) Selective loss of AKR1C1 and AKR1C2 in breast cancer and their potential effect on progesterone signaling. Cancer Res 64:7610–7617. https://doi.org/10.1158/0008-5472.can-04-1608
Jiang Y, Li Y, Cheng J, Ma J, Li Q, Pang T (2020) Upregulation of AKR1C1 in mesenchymal stromal cells promotes the survival of acute myeloid leukaemia cells. Br J Haematol. https://doi.org/10.1111/bjh.16253
Kalliala I et al (2020) Incidence and mortality from cervical cancer and other malignancies after treatment of cervical intraepithelial neoplasia: a systematic review and meta-analysis of the literature. Ann Oncol 31:213–227. https://doi.org/10.1016/j.annonc.2019.11.004
Kizub DA, Zujewski J, Gralow JR, Ndoh K, Soko U, Dvaladze AL (2020) patient advocacy approaches to improving care for breast and cervical cancer in East and Southern Africa. JCO Global Oncol 6:49–55. https://doi.org/10.1200/JGO.19.00219
Lewis MJ, Wiebe JP, Heathcote JG (2004) Expression of progesterone metabolizing enzyme genes (AKR1C1, AKR1C2, AKR1C3, SRD5A1, SRD5A2) is altered in human breast carcinoma. BMC Cancer 4:27. https://doi.org/10.1186/1471-2407-4-27
Li C, Ao H, Chen G, Wang F, Li F (2019a) The interaction of CDH20 with beta-catenin inhibits cervical cancer cell migration and invasion via TGF-beta/Smad/SNAIL mediated EMT. Frontiers Oncol 9:1481. https://doi.org/10.3389/fonc.2019.01481
Li Y, Chen G, Yan Y, Fan Q (2019b) CASC15 promotes epithelial to mesenchymal transition and facilitates malignancy of hepatocellular carcinoma cells by increasing TWIST1 gene expression via miR-33a-5p sponging. Eur J Pharmacol 860:172589. https://doi.org/10.1016/j.ejphar.2019.172589
Li T et al (2020) Clinical performance of Onclarity HPV assay and Cobas HPV test in detection of cervical precancer and cancer in Chinese women. Gynecol Oncol. https://doi.org/10.1016/j.ygyno.2020.01.011
Lin J et al (2019) TRIB3 stabilizes high TWIST1 expression to promote rapid APL progression and ATRA. Resist Clin Cancer Res 25:6228–6242. https://doi.org/10.1158/1078-0432.ccr-19-0510
Pan J et al (2020) lncRNA JPX/miR-33a-5p/Twist1 axis regulates tumorigenesis and metastasis of lung cancer by activating Wnt/beta-catenin signaling. Mol Cancer 19:9. https://doi.org/10.1186/s12943-020-1133-9
Penning TM et al (2000) Human 3alpha-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones. Biochem J 351:67–77. https://doi.org/10.1042/0264-6021:3510067
Rizner TL, Smuc T, Rupreht R, Sinkovec J, Penning TM (2006) AKR1C1 and AKR1C3 may determine progesterone and estrogen ratios in endometrial cancer. Mol Cell Endocrinol 248:126–135. https://doi.org/10.1016/j.mce.2005.10.009
Tian H, Li X, Jiang W, Lv C, Sun W, Huang C, Chen R (2016) High expression of AKR1C1 is associated with proliferation and migration of small-cell lung cancer. Lung Cancer 7:53–61. https://doi.org/10.2147/lctt.s90694
Wang Q et al (2020) CLEC5A promotes the proliferation of gastric cancer cells by activating the PI3K/AKT/mTOR pathway. Biochem Biophys Res Commun. https://doi.org/10.1016/j.bbrc.2019.10.122
Wenners A et al (2016) Stromal markers AKR1C1 and AKR1C2 are prognostic factors in primary human breast cancer. Int J Clin Oncol 21:548–556. https://doi.org/10.1007/s10147-015-0924-2
Woo S, Gao H, Henderson D, Zacharias W, Liu G, Tran QT, Prasad GL (2017) AKR1C1 as a biomarker for differentiating the biological effects of combustible from non-combustible tobacco products. Genes. https://doi.org/10.3390/genes8050132
Xiong H et al (2017) Twist1 enhances hypoxia induced radioresistance in cervical cancer cells by promoting nuclear EGFR localization. J Cancer 8:345–353. https://doi.org/10.7150/jca.16607
Yun H, Xie J, Olumi AF, Ghosh R, Kumar AP (2015) Activation of AKR1C1/ERbeta induces apoptosis by downregulation of c-FLIP in prostate cancer cells: a prospective therapeutic opportunity. Oncotarget 6:11600–11613
Zeng CM, Chang LL, Ying MD, Cao J, He QJ, Zhu H, Yang B (2017) Aldo-Keto reductase AKR1C1-AKR1C4: functions, regulation, and intervention for anti-cancer therapy. Frontiers Pharmacol 8:119. https://doi.org/10.3389/fphar.2017.00119
Zhang L, Liu X, Song L, Zhai H, Chang C (2020) MAP7 promotes migration and invasion and progression of human cervical cancer through modulating the autophagy. Cancer Cell Int 20:17. https://doi.org/10.1186/s12935-020-1095-4
Zhao SF, Wang SG, Zhao ZY, Li WL (2019) AKR1C1-3, notably AKR1C3, are distinct biomarkers for liver cancer diagnosis and prognosis: database mining in malignancies. Oncol Lett 18:4515–4522. https://doi.org/10.3892/ol.2019.10802
Zhu H et al (2018) AKR1C1 activates STAT3 to promote the metastasis of non-small cell lung cancer. Theranostics 8:676–692. https://doi.org/10.7150/thno.21463
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ZHW conceived and designed the experiments, XW and YYL analyzed and interpreted the results of the experiments, ZQT and CL performed the experiments.
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Figure S1: AKR1C2 and AKR1C3 expression was enhanced in tumor tissues of CC patients
. Quantitative PCR assays revealed the obviously increased mRNA levels of AKR1C2 (A) and AKR1C3 (B) in 71 human cervical cancer tissues. Results are presented as mean ± SEM, ** p < 0.01. (JPG 301 kb)
Figure S2: The expression of AKR1C2 and AKR2C3 in HeLa and SiHa cells
. Quantitative PCR assays were conducted to detect the expression levels of AKR1C2 (A) and AKR1C3 (B) in different cervical cancer cell lines including SiHa, C33A, Caski and HeLa cells. Results are presented as mean ± SEM, ** p < 0.01. (JPG 209 kb)
Figure S3: TWIST expression was enhanced in tumor tissues compared to normal tissues of CC patients
. Quantitative PCR assays were conducted to detect the expression levels of TWIST in tumor tissues and normal tissues Results are presented as mean ± SEM, ** p < 0.01. (JPG 161 kb)
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Wei, X., Wei, Z., Li, Y. et al. AKR1C1 Contributes to Cervical Cancer Progression via Regulating TWIST1 Expression. Biochem Genet 59, 516–530 (2021). https://doi.org/10.1007/s10528-020-10014-x
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DOI: https://doi.org/10.1007/s10528-020-10014-x