HLF Promotes Ovarian Cancer Progression and Chemoresistance Via Regulating Hippo Signaling Pathway

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2023 Sep 14

PMID 37709768

Authors

Tao Han

Tingsong Chen

Lujun Chen

Kerui Li

Daimin Xiang

Lei Dou

Hengyu Li

Yubei Gu

Affiliations

Soon will be listed here.

Abstract

Hepatic leukemia factor (HLF) is aberrantly expressed in human malignancies. However, the role of HLF in the regulation of ovarian cancer (OC) remains unknown. Herein, we reported that HLF expression was upregulated in OC tissues and ovarian cancer stem cells (CSCs). Functional studies have revealed that HLF regulates OC cell stemness, proliferation, and metastasis. Mechanistically, HLF transcriptionally activated Yes-associated protein 1 (YAP1) expression and subsequently modulated the Hippo signaling pathway. Moreover, we found that miR-520e directly targeted HLF 3'-UTR in OC cells. miR-520e expression was negatively correlated with HLF and YAP1 expression in OC tissues. The combined immunohistochemical (IHC) panels exhibited a better prognostic value for OC patients than any of these components alone. Importantly, the HLF/YAP1 axis determines the response of OC cells to carboplatin treatment and HLF depletion or the YAP1 inhibitor verteporfin abrogated carboplatin resistance. Analysis of patient-derived xenografts (PDXs) further suggested that HLF might predict carboplatin benefits in OC patients. In conclusion, these findings suggest a crucial role of the miR-520e/HLF/YAP1 axis in OC progression and chemoresistance, suggesting potential therapeutic targets for OC.

Citing Articles

Construction of an anaplastic thyroid cancer stratification signature to guide immune therapy selection and validation of the pivotal gene HLF through experiments.

Pengping L, Kexin Y, Yuwei X, Ke S, Rongguo L, Zhenyu W Front Immunol. 2025; 15:1478904.

PMID: 39872516 PMC: 11769983. DOI: 10.3389/fimmu.2024.1478904.

Insights into the transcriptomic responses of silver-lipped pearl oysters Pinctada maxima exposed to a simulated large-scale seismic survey.

Dang C, Severn-Ellis A, Bayer P, Anderson N, Gholipour-Kanani H, Batley J BMC Genomics. 2024; 25(1):1188.

PMID: 39639203 PMC: 11622493. DOI: 10.1186/s12864-024-11091-7.

Integrated machine learning and Mendelian randomization reveal PALMD as a prognostic biomarker for nonspecific orbital inflammation.

Wu Z, Liu X, Tan K, Yao X, Peng Q Sci Rep. 2024; 14(1):24020.

PMID: 39402101 PMC: 11473641. DOI: 10.1038/s41598-024-74409-1.

17β-Estradiol, through activating the G protein-coupled estrogen receptor, exacerbates the complication of benign prostatic hyperplasia in type 2 diabetes mellitus patients by inducing prostate proliferation.

Yang T, Qiu Z, Shen J, He Y, Yin L, Chen L J Pharm Anal. 2024; 14(9):100962.

PMID: 39350964 PMC: 11440253. DOI: 10.1016/j.jpha.2024.03.003.

Deciphering the role of HLF in idiopathic orbital inflammation: integrative analysis via bioinformatics and machine learning techniques.

Wu Z, Song Q, Liu M, Hu Y, Peng X, Zhang Z Sci Rep. 2024; 14(1):19346.

PMID: 39164324 PMC: 11336107. DOI: 10.1038/s41598-024-68890-x.

References

Xu X, Wang B, Liu Y, Jing T, Xu G, Zhang L . ETV4 potentiates nuclear YAP retention and activities to enhance the progression of hepatocellular carcinoma. Cancer Lett. 2022; 537:215640. DOI: 10.1016/j.canlet.2022.215640. View

Tocci P, Cianfrocca R, Sestito R, Rosano L, Di Castro V, Blandino G . Endothelin-1 axis fosters YAP-induced chemotherapy escape in ovarian cancer. Cancer Lett. 2020; 492:84-95. DOI: 10.1016/j.canlet.2020.08.026. View

Wang Z, Li X, Chen H, Han L, Ji X, Wang Q . Decreased HLF Expression Predicts Poor Survival in Lung Adenocarcinoma. Med Sci Monit. 2021; 27:e929333. PMC: 8127640. DOI: 10.12659/MSM.929333. View

Hunger S, Ohyashiki K, Toyama K, Cleary M . Hlf, a novel hepatic bZIP protein, shows altered DNA-binding properties following fusion to E2A in t(17;19) acute lymphoblastic leukemia. Genes Dev. 1992; 6(9):1608-20. DOI: 10.1101/gad.6.9.1608. View

Zhang Y, Wang Y, Zhao G, Tanner E, Adli M, Matei D . FOXK2 promotes ovarian cancer stemness by regulating the unfolded protein response pathway. J Clin Invest. 2022; 132(10). PMC: 9106354. DOI: 10.1172/JCI151591. View

Zivanovic O, Chi D, Zhou Q, Iasonos A, Konner J, Makker V . Secondary Cytoreduction and Carboplatin Hyperthermic Intraperitoneal Chemotherapy for Platinum-Sensitive Recurrent Ovarian Cancer: An MSK Team Ovary Phase II Study. J Clin Oncol. 2021; 39(23):2594-2604. PMC: 8330970. DOI: 10.1200/JCO.21.00605. View

Siegel R, Miller K, Fuchs H, Jemal A . Cancer Statistics, 2021. CA Cancer J Clin. 2021; 71(1):7-33. DOI: 10.3322/caac.21654. View

Zhang X, George J, Deb S, Degoutin J, Takano E, Fox S . The Hippo pathway transcriptional co-activator, YAP, is an ovarian cancer oncogene. Oncogene. 2011; 30(25):2810-22. DOI: 10.1038/onc.2011.8. View

Han T, Xiang D, Sun W, Liu N, Sun H, Wen W . PTPN11/Shp2 overexpression enhances liver cancer progression and predicts poor prognosis of patients. J Hepatol. 2015; 63(3):651-60. DOI: 10.1016/j.jhep.2015.03.036. View

10.

Park H, Kim Y, Yu B, Moroishi T, Mo J, Plouffe S . Alternative Wnt Signaling Activates YAP/TAZ. Cell. 2015; 162(4):780-94. PMC: 4538707. DOI: 10.1016/j.cell.2015.07.013. View

11.

Liu Y, Zhao R, Liu C, Zhou J, Yang L, Li L . MiR-320b and miR-320d as Biomarkers to Predict and Participate in the Formation of Platinum Resistance in Ovarian Cancer Patients. Front Oncol. 2022; 12:881496. PMC: 9110861. DOI: 10.3389/fonc.2022.881496. View

12.

Liu Z, Li J, Ding Y, Ma M, Chen J, Lei W . USP49 mediates tumor progression and poor prognosis through a YAP1-dependent feedback loop in gastric cancer. Oncogene. 2022; 41(18):2555-2570. DOI: 10.1038/s41388-022-02267-0. View

13.

Xiang D, Sun W, Ning B, Zhou T, Li X, Zhong W . The HLF/IL-6/STAT3 feedforward circuit drives hepatic stellate cell activation to promote liver fibrosis. Gut. 2017; 67(9):1704-1715. DOI: 10.1136/gutjnl-2016-313392. View

14.

Falandry C, Rousseau F, Mouret-Reynier M, Tinquaut F, Lorusso D, Herrstedt J . Efficacy and Safety of First-line Single-Agent Carboplatin vs Carboplatin Plus Paclitaxel for Vulnerable Older Adult Women With Ovarian Cancer: A GINECO/GCIG Randomized Clinical Trial. JAMA Oncol. 2021; 7(6):853-861. PMC: 8063137. DOI: 10.1001/jamaoncol.2021.0696. View

15.

Omori H, Nishio M, Masuda M, Miyachi Y, Ueda F, Nakano T . YAP1 is a potent driver of the onset and progression of oral squamous cell carcinoma. Sci Adv. 2020; 6(12):eaay3324. PMC: 7080500. DOI: 10.1126/sciadv.aay3324. View

16.

Li H, Yang P, Wang J, Zhang J, Ma Q, Jiang Y . HLF regulates ferroptosis, development and chemoresistance of triple-negative breast cancer by activating tumor cell-macrophage crosstalk. J Hematol Oncol. 2022; 15(1):2. PMC: 8740349. DOI: 10.1186/s13045-021-01223-x. View

17.

Khan M, Vikramdeo K, Sudan S, Singh S, Wilhite A, Dasgupta S . Platinum-resistant ovarian cancer: From drug resistance mechanisms to liquid biopsy-based biomarkers for disease management. Semin Cancer Biol. 2021; 77:99-109. PMC: 8665066. DOI: 10.1016/j.semcancer.2021.08.005. View

18.

Wen Y, Hou Y, Yi X, Sun S, Guo J, He X . EZH2 activates CHK1 signaling to promote ovarian cancer chemoresistance by maintaining the properties of cancer stem cells. Theranostics. 2021; 11(4):1795-1813. PMC: 7778604. DOI: 10.7150/thno.48101. View

19.

Yokomizo T, Watanabe N, Umemoto T, Matsuo J, Harai R, Kihara Y . Hlf marks the developmental pathway for hematopoietic stem cells but not for erythro-myeloid progenitors. J Exp Med. 2019; 216(7):1599-1614. PMC: 6605751. DOI: 10.1084/jem.20181399. View

20.

Hall C, Wang R, Miao J, Oliva E, Shen X, Wheeler T . Hippo pathway effector Yap is an ovarian cancer oncogene. Cancer Res. 2010; 70(21):8517-25. PMC: 2970655. DOI: 10.1158/0008-5472.CAN-10-1242. View