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PTEN gene and AKT/mTOR pathway in gynecological cancers and cancer immune escape

  • Xi Zeng1,2
  • Ming-Rong Xi1,2
  • Hong-Wei Ma1,2,*,

1Department of Gynecology and Obstetrics, The West China Second University Hospital, Sichuan University, 610000 Chengdu, Sichuan, China

2Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, 610000 Chengdu, Sichuan, China

DOI: 10.22514/ejgo.2022.024 Vol.43,Issue 4,August 2022 pp.19-24

Submitted: 05 May 2022 Accepted: 10 June 2022

Published: 15 August 2022

*Corresponding Author(s): Hong-Wei Ma E-mail:


Gynecological cancers (GCs) include cervical, uterine, ovarian, vulvar and vaginal cancer. For women in China, 2 of the 10 most common cancers are GCs (8th: cervical cancer, incidence rate: 3.96%; 10th: ovarian cancer, incidence rate: 2.91%). These cancers can lead to enormous psychological and economic burdens. Phosphatase and tensin homolog (PTEN) gene and protein kinase B (AKT) and mammalian target of rapamycin (mTOR) pathway are widely involved in the development of GCs, and an imbalance in regulatory T cells (Treg) in the cancer micro-environment mediated by PTEN and AKT/mTOR pathway was shown to lead to cancer cell immune escape, growth and metastasis. Considering that the pathogenesis of PTEN and AKT/mTOR pathway in GCs and cancer immune escape remains unclear, this review article intends to provide an update in this field. We made a comprehensive search of several databases, including Web of Science, MEDLINE, Ovid and Cochrane Database of Systematic Reviews, was conducted from inception to March 2022. The search strategy included the combinations of the following medical terms: gynecological cancers, cervical cancer, uterine cancer, ovarian cancer, vulvar cancer, vaginal cancer, PTEN gene, AKT/mTOR pathway, and cancer immune escape. We found that currently the mechanism of the PTEN gene and AKT/mTOR pathway in GCs is not fully clear. However, the activation of the AKT/mTOR signaling pathway and imbalance of Treg cell in the micro-environment caused by the function loss of PTEN is involved in the occurrence and development of GCs, and related to the prognosis of patients. This review article presented the latest research progress on the PTEN gene and AKT/mTOR pathway in GCs and cancer cell immune escape.


PTEN/AKT-mTOR pathway; Malignant gynecological cancers; Tumor microenvironment; Immune escape; Signaling pathways

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Xi Zeng,Ming-Rong Xi,Hong-Wei Ma. PTEN gene and AKT/mTOR pathway in gynecological cancers and cancer immune escape. European Journal of Gynaecological Oncology. 2022. 43(4);19-24.


[1] Jiang X, Tang H, Chen T. Epidemiology of gynecologic cancers in China. Journal of Gynecologic Oncology. 2018; 29: e7.

[2] He R, Zhu B, Liu J, Zhang N, Zhang W, Mao Y. Women’s cancers in China: a spatio-temporal epidemiology analysis. BMC Women’S Health. 2021; 21: 116.

[3] Zheng R, Sun K, Zhang S, Zeng H, Zou X, Chen R, et al. Report of cancer epidemiology in China, 2015. Chinese Journal of Oncology. 2019; 41: 19–28. (In Chinese)

[4] Arneth B. Tumor microenvironment. Medicina (Kaunas). 2020; 56: 15.

[5] Pietras K, Östman A. Hallmarks of cancer: interactions with the tumor stroma. Experimental Cell Research. 2010; 316: 1324–1331.

[6] Song N, Zhang T, Xu X, Lu Z, Yu X, Fang Y, et al. miR-21 protects against ischemia/reperfusion-induced acute kidney injury by preventing epithelial cell apoptosis and inhibiting dendritic cell maturation. Frontiers in Physiology. 2018; 9: 790.

[7] Vidotto T, Melo CM, Castelli E, Koti M, Dos Reis RB, Squire JA. Emerging role of PTEN loss in evasion of the immune response to tumours. British Journal of Cancer. 2020; 122: 1732–1743.

[8] Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997; 275: 1943–1947.

[9] Wang Y, Liu Y, Du X, Ma H, Yao J. Berberine reverses doxorubicin resistance by inhibiting autophagy through the PTEN/Akt/mTOR signaling pathway in breast cancer. OncoTargets and Therapy. 2020; 13: 1909–1919.

[10] Ortega-Molina A, Serrano M. PTEN in cancer, metabolism, and aging. Trends in Endocrinology & Metabolism. 2013; 24: 184–189.

[11] Akca H, Demiray A, Tokgun O, Yokota J. Invasiveness and anchorage independent growth ability augmented by PTEN inactivation through the PI3K/AKT/NFkB pathway in lung cancer cells. Lung Cancer. 2011; 73: 302–309.

[12] Jiang N, Dai Q, Su X, Fu J, Feng X, Peng J. Role of PI3K/AKT pathway in cancer: the framework of malignant behavior. Molecular Biology Reports. 2020; 47: 4587–4629.

[13] Liu R, Chen Y, Liu G, Li C, Song Y, Cao Z, et al. PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers. Cell Death & Disease. 2020; 11: 797.

[14] Zou Z, Tao T, Li H, Zhu X. mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges. Cell & Bioscience. 2020; 10: 1–11.

[15] Liu GY, Sabatini DM. MTOR at the nexus of nutrition, growth, ageing and disease. Nature Reviews Molecular Cell Biology. 2020; 21: 183–203.

[16] Chen Y, Zhou X. Research progress of mTOR inhibitors. European Journal of Medicinal Chemistry. 2020; 208: 112820.

[17] Xu F, Na L, Li Y, Chen L. Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours. Cell & Bioscience. 2020; 10: 1–12.

[18] Takahara T, Amemiya Y, Sugiyama R, Maki M, Shibata H. Amino acid-dependent control of mTORC1 signaling: a variety of regulatory modes. Journal of Biomedical Science. 2020; 27: 87.

[19] Fu W, Hall MN. Regulation of mTORC2 signaling. Genes. 2020; 11: 1045.

[20] Zhang Z, Chen Q, Zhang J, Wang Y, Hu X, Yin S, et al. Associations of genetic polymorphisms in pTEN/AKT/mTOR signaling pathway genes with cancer risk: a meta-analysis in Asian population. Scientific Reports. 2017; 7: 17844.

[21] Lim HJ, Crowe P, Yang J. Current clinical regulation of PI3K/PTEN/Akt/mTOR signalling in treatment of human cancer. Journal of Cancer Research and Clinical Oncology. 2015; 141: 671–689.

[22] Memarzadeh S, Zong Y, Janzen DM, Goldstein AS, Cheng D, Kurita T, et al. Cell-autonomous activation of the PI3-kinase pathway initiates endometrial cancer from adult uterine epithelium. Proceedings of the National Academy of Sciences. 2010; 107: 17298–17303.

[23] Janku F. Phosphoinositide 3-kinase (PI3K) pathway inhibitors in solid tumors: from laboratory to patients. Cancer Treatment Reviews. 2017; 59: 93–101.

[24] Barra F, Evangelisti G, Ferro Desideri L, Di Domenico S, Ferraioli D, Vellone VG, et al. Investigational PI3K/AKT/mTOR inhibitors in development for endometrial cancer. Expert Opinion on Investigational Drugs. 2019; 28: 131–142.

[25] Hu M, Zhu S, Xiong S, Xue X, Zhou X. MicroRNAs and the PTEN/PI3K/Akt pathway in gastric cancer. Oncology Reports. 2019; 41: 1439–1454.

[26] Benavides-Serrato A, Lee J, Holmes B, Landon KA, Bashir T, Jung ME, et al. Correction: specific blockade of Rictor-mTOR association inhibits mTORC2 activity and is cytotoxic in glioblastoma. PloS One. 2019; 14: e0212160.

[27] Wang M, Sun R, Zhou X, Zhang M, Lu J, Yang Y, et al. Epithelial cell adhesion molecule overexpression regulates epithelial-mesenchymal transition, stemness and metastasis of nasopharyngeal carcinoma cells via the PTEN/AKT/mTOR pathway. Cell Death & Disease. 2018; 9: 2.

[28] Xing D, Fadare O. Molecular events in the pathogenesis of vulvar squamous cell carcinoma. Seminars in Diagnostic Pathology. 2021; 38: 50–61.

[29] de Melo AC, Paulino E, Garces ÁHI. A review of mTOR pathway inhibitors in gynecologic cancer. Oxidative Medicine and Cellular Longevity. 2017; 2017: 1–8.

[30] Zheng Y, Yang X, Wang C, Zhang S, Wang Z, Li M, et al. HDAC6, modulated by miR-206, promotes endometrial cancer progression through the PTEN/AKT/mTOR pathway. Scientific Reports. 2020; 10: 3576.

[31] S. Dhanalakshmi, N. Harikrishnan, N. Janani, P. Shakthi priya, M. Srinivasan, A. Karthikeyan, et al. The overview: recent studies on endometrial cancer. Research Journal of Pharmacy and Technology. 2021; 14: 3998–4002.

[32] Liu H, Zhang L, Zhang X, Cui Z. PI3K/AKT/mTOR pathway promotes progestin resistance in endometrial cancer cells by inhibition of autophagy. OncoTargets and Therapy. 2017; 10: 2865.

[33] Gao Y, Lin P, Lydon JP, Li Q. Conditional abrogation of transforming growth factor-β receptor 1 in PTEN-inactivated endometrium promotes endometrial cancer progression in mice. The Journal of Pathology. 2017; 243: 89–99.

[34] Cheng H, Liu P, Zhang F, Xu E, Symonds L, Ohlson CE, et al. A genetic mouse model of invasive endometrial cancer driven by concurrent loss of Pten and Lkb1 is highly responsive to mTOR inhibition. Cancer Research. 2014; 74: 15–23.

[35] Bajwa P, Nielsen S, Lombard JM, Rassam L, Nahar P, Rueda BR, et al. Overactive mTOR signaling leads to endometrial hyperplasia in aged women and mice. Oncotarget. 2017; 8: 7265–7275.

[36] Bian X, Gao J, Luo F, Rui C, Zheng T, Wang D, et al. PTEN deficiency sensitizes endometrioid endometrial cancer to compound PARP-PI3K inhibition but not PARP inhibition as monotherapy. Oncogene. 2018; 37: 341–351.

[37] Qin J, Fu M, Wang J, Huang F, Liu H, Huangfu M, et al. PTEN/AKT/mTOR signaling mediates anticancer effects of epigallocatechin-3-gallate in ovarian cancer. Oncology Reports. 2020; 43: 1885–1896.

[38] Ghoneum A, Said N. PI3K-AKT-mTOR and NFκB pathways in ovarian cancer: implications for targeted therapeutics. Cancers. 2019; 11: 949.

[39] Jin C, Liu Z, Li Y, Bu H, Wang Y, Xu Y, et al. PCNA-associated factor P15PAF, targeted by FOXM1, predicts poor prognosis in high-grade serous ovarian cancer patients. International Journal of Cancer. 2018; 143: 2973–2984.

[40] Nero C, Ciccarone F, Pietragalla A, Scambia G. PTEN and gynecological cancers. Cancers. 2019; 11: 1458.

[41] Bossler F, Hoppe-Seyler K, Hoppe-Seyler F. PI3K/AKT/mTOR signaling regulates the virus/host cell crosstalk in HPV-positive cervical cancer cells. International Journal of Molecular Sciences. 2019; 20: 2188.

[42] Chen F-X. Changes of PI3K/AKT/mTOR signaling pathway in the progression of cervical cancer and its target genes. Journal of Hainan Medical University. 2018; 24: 59–62.

[43] Bahrami A, Hasanzadeh M, Hassanian SM, ShahidSales S, Ghayour-Mobarhan M, Ferns GA, et al. The potential value of the PI3K/Akt/mTOR signaling pathway for assessing prognosis in cervical cancer and as a target for therapy. Journal of Cellular Biochemistry. 2017; 118: 4163–4169.

[44] Zięba S, Kowalik A, Zalewski K, Rusetska N, Goryca K, Piaścik A, et al. Somatic mutation profiling of vulvar cancer: exploring therapeutic targets. Gynecologic Oncology. 2018; 150: 552–561.

[45] Allavena P, Sica A, Solinas G, Porta C, Mantovani A. The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages. Critical Reviews in Oncology/Hematology. 2008; 66: 1–9.

[46] Lei X, Lei Y, Li J, Du W, Li R, Yang J, et al. Immune cells within the tumor microenvironment: biological functions and roles in cancer immunotherapy. Cancer Letters. 2020; 470: 126–133.

[47] Paluskievicz CM, Cao X, Abdi R, Zheng P, Liu Y, Bromberg JS. T regulatory cells and priming the suppressive tumor microenvironment. Frontiers in Immunology. 2019; 10: 2453.

[48] Wei T, Zhong W, Li Q. Role of heterogeneous regulatory T cells in the tumor microenvironment. Pharmacological Research. 2020; 153: 104659.

[49] Tanaka A, Sakaguchi S. Targeting Treg cells in cancer immunotherapy. European Journal of Immunology. 2019; 49: 1140–1146.

[50] Ou Y, Cannon MJ, Nakagawa M. Regulatory T cells in gynecologic cancer. MOJ Immunology. 2018; 6: 34.

[51] Gandhi GR, Neta MTSL, Sathiyabama RG, Quintans JDSS, de Oliveira e Silva AM, Araújo AADS, et al. Flavonoids as Th1/Th2 cytokines immunomodulators: a systematic review of studies on animal models. Phytomedicine. 2018; 44: 74–84.

[52] Munn DH, Sharma MD, Johnson TS. Treg destabilization and reprogram-ming: implications for cancer immunotherapy. Cancer Research. 2018; 78: 5191–5199.

[53] You D, Wang Y, Zhang Y, Li Q, Yu X, Yuan M, et al. Association of Foxp3 promoter polymorphisms with susceptibility to endometrial cancer in the Chinese Han women. Medicine. 2018; 97: e0582.

[54] Bruno V, Corrado G, Baci D, Chiofalo B, Carosi MA, Ronchetti L, et al. Endometrial cancer immune escape mechanisms: let us learn from the fetal—maternal interface. Frontiers in Oncology. 2020; 10: 156.

[55] Torrey H, Butterworth J, Mera T, Okubo Y, Wang L, Baum D, et al. Targeting TNFR2 with antagonistic antibodies inhibits proliferation of ovarian cancer cells and tumor-associated Tregs. Science Signaling. 2017; 10: eaaf8608.

[56] Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature Medicine. 2004; 10: 942–949.

[57] Lin Z, Huang L, Li SL, Gu J, Cui X, Zhou Y. PTEN loss correlates with T cell exclusion across human cancers. BMC Cancer. 2021; 21: 429.

[58] Zhang W, Hou F, Zhang Y, Tian Y, Jiao J, Ma D, et al. Changes of Th17/Tc17 and Th17/Treg cells in endometrial carcinoma. Gynecologic Oncology. 2014; 132: 599–605.

[59] Driessen GJ, IJspeert H, Wentink M, Yntema HG, van Hagen PM, van Strien A, et al. Increased PI3K/Akt activity and deregulated humoral immune response in human PTEN deficiency. Journal of Allergy and Clinical Immunology. 2016; 138: 1744–1747. e1745.

[60] Munn DH, Sharma MD, Johnson TS, Rodriguez P. IDO, PTEN-expressing Tregs and control of antigen-presentation in the murine tumor microenvironment. Cancer Immunology, Immunotherapy. 2017; 66: 1049–1058.

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