Horm Metab Res 2023; 55(06): 413-419
DOI: 10.1055/a-2044-9227
Original Article: Endocrine Research

CCND1-Induced Autophagy Contributes to Lymph Node Metastasis in Endometrial Cancer

Yi Su
1   Shandong University Cancer Center, Jinan, China
2   Department of Radiotherapy, Yantai Yuhuangding Hospital, Yantai, China
,
Haonan Zhou
3   The First Clinical Medical School, Gansu University of Chinese Medicine, Lanzhou, China
,
Zhao Ma
2   Department of Radiotherapy, Yantai Yuhuangding Hospital, Yantai, China
,
Jing Liu*
4   Department of Pathology, Yantai Yuhuangding Hospital, Yantai, China
,
Chen Li*
2   Department of Radiotherapy, Yantai Yuhuangding Hospital, Yantai, China
› Author Affiliations
Funding Information The Science and Technology Project in Yantai — 2019YT0600074

Abstract

Endometrial cancer with lymph node metastasis shows poor prognosis, while the biomarker to predict the metastasis is lacking. The relative mRNA or protein expression of cyclin D1 (CCND1) and autophagy-related molecules were detected in real-time PCR and Western blot. Correlation analysis was applied to identify any significant patterns, and receiver operating characteristics (ROC) was performed to assess the prediction value. CCND1 vector was transfected in Ishikawa (ISK) cells, and the relative expression of autophagy-related molecules was detected with Western blot. CCND1 was overexpressed in endometrial cancer and correlated with lymph node metastasis. ROC analysis found that CCND1 had a predictive value to discriminate tumors from normal tissues (cut off=1.455; sensitivity, 71%; specificity, 84%; area under curve (AUC) 0.82; p<0.001) and had a predictive value to indicate metastasis (cut off=1.871; sensitivity, 54.17%; specificity, 75%; AUC 0.674; p=0.003). Increased BECLIN1 (r=0.39, p<0.001) and ATG5 (r=0.41, p<0.001) expression were positively correlated to CCND1. On the other hand, the relative protein expression of CCND1, BECLIN1, ATG5, ATG7, and LC3 I/II were also increased in tumor tissues. CCND1 overexpressed ISK cells showed upregulated BECLIN1, ATG5, ATG7, and LC3 I/II expression. CCND1 promoted autophagy may contribute to lymph node metastasis in endometrial cancer.

* Co-corresponding authors.




Publication History

Received: 01 December 2022

Accepted after revision: 23 February 2023

Article published online:
05 April 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Zhang C, Zheng W.. High-grade endometrial carcinomas: morphologic spectrum and molecular classification. Semin Diagn Pathol 2022; 39: 176-186
  • 2 Lu KH, Broaddus RR.. Endometrial cancer. N Engl J Med 2020; 383: 2053-2064
  • 3 Voelker R.. Immunotherapy approved for endometrial cancer. JAMA 2021; 325: 2143
  • 4 Ravegnini G, Gorini F, De Crescenzo E. et al. Can miRNAs be useful biomarkers in improving prognostic stratification in endometrial cancer patients? An update review. Int J Cancer 2022; 150: 1077-1090
  • 5 Li W, Jiang J, Fu Y. et al. Implications of isolated para-aortic lymph node metastasis in endometrial cancer: a large-scale, multicenter, and retrospective study. Front Med (Lausanne) 2021; 8: 754890
  • 6 Kasius JC, Pijnenborg JMA, Lindemann K. et al. Risk stratification of endometrial cancer patients: FIGO stage, biomarkers and molecular classification. Cancers (Basel) 2021; 13: 5848
  • 7 Cai Z, Wang J, Li Y. et al. Overexpressed cyclin D1 and CDK4 proteins are responsible for the resistance to CDK4/6 inhibitor in breast cancer that can be reversed by PI3K/mTOR inhibitors. Sci China Life Sci 2023; 66: 94-109
  • 8 Go SI, Ko GH, Lee WS. et al. Cyclin D1 serves as a poor prognostic biomarker in stage I gastric cancer. Curr Issues Mol Biol 2022; 44: 1395-1406
  • 9 Jun SY, Kim J, Yoon N. et al. Prognostic potential of cyclin D1 expression in colorectal cancer. J Clin Med 2023; 12: 572
  • 10 Shan KZ, Yang SF, Deng YJ. et al. E2F1-induced long non-coding RNA MCF2L-AS1 modulates Cyclin D1 mRNA stability through ELAVL1 to induce Gefitinib resistance in non-small cell lung cancer. Acta Biochim Pol 2022; 69: 795-804
  • 11 Lebovitz CB, Robertson AG, Goya R. et al. Cross-cancer profiling of molecular alterations within the human autophagy interaction network. Autophagy 2015; 11: 1668-1687
  • 12 Nuñez-Olvera SI, Gallardo-Rincón D, Puente-Rivera J. et al. Autophagy machinery as a promising therapeutic target in endometrial cancer. Front Oncol 2019; 9: 1326
  • 13 Yang S, Wang H, Li D. et al. Role of endometrial autophagy in physiological and pathophysiological processes. J Cancer 2019; 10: 3459-3471
  • 14 Orfanelli T, Jeong JM, Doulaveris G. et al. Involvement of autophagy in cervical, endometrial and ovarian cancer. Int J Cancer 2014; 135: 519-528
  • 15 Wang X, Dai C, Ye M. et al. Prognostic value of an autophagy-related long-noncoding-RNA signature for endometrial cancer. Aging (Albany N Y) 2021; 13: 5104-5119
  • 16 Moreno-Bueno G, Rodríguez-Perales S, Sánchez-Estévez C. et al. Cyclin D1 gene (CCND1) mutations in endometrial cancer. Oncogene 2003; 22: 6115-6118
  • 17 Xu J, Lin DI.. Oncogenic c-terminal cyclin D1 (CCND1) mutations are enriched in endometrioid endometrial adenocarcinomas. PLoS One 2018; 13: e0199688
  • 18 Ikeda Y, Oda K, Hiraike-Wada O. et al. Cyclin D1 harboring the T286I mutation promotes oncogenic activation in endometrial cancer. Oncol Rep 2013; 30: 584-588
  • 19 Kang S, Kim JW, Park NH. et al. Cyclin D1 polymorphism and the risk of endometrial cancer. Gynecol Oncol 2005; 97: 431-435
  • 20 Fusté NP, Fernández-Hernández R, Cemeli T. et al. Cytoplasmic cyclin D1 regulates cell invasion and metastasis through the phosphorylation of paxillin. Nat Commun 2016; 7: 11581
  • 21 Seiler R, Thalmann GN, Rotzer D. et al. CCND1/CyclinD1 status in metastasizing bladder cancer: a prognosticator and predictor of chemotherapeutic response. Mod Pathol 2014; 27: 87-95
  • 22 Xia H, Green DR, Zou W.. Autophagy in tumour immunity and therapy. Nat Rev Cancer 2021; 21: 281-297
  • 23 Deretic V.. Autophagy in inflammation, infection, and immunometabolism. Immunity 2021; 54: 437-453
  • 24 Nardone V, Barbarino M, Angrisani A. et al. CDK4, CDK6/cyclin-D1 complex inhibition and radiotherapy for cancer control: a role for autophagy. Int J Mol Sci 2021; 22: 8391
  • 25 Casimiro MC, Di Sante G, Di Rocco A. et al. Cyclin D1 restrains oncogene-induced autophagy by regulating the AMPK-LKB1 signaling axis. Cancer Res 2017; 77: 3391-3405
  • 26 Zhang H.. CCND1 silencing suppresses liver cancer stem cell differentiation through inhibiting autophagy. Hum Cell 2020; 33: 140-147
  • 27 Wu T, Li Y, Gong L. et al. Multi-step process of human breast carcinogenesis: a role for BRCA1, BECN1, CCND1, PTEN and UVRAG. Mol Med Rep 2012; 5: 305-312
  • 28 Wu SY, Lan SH, Liu HS.. Degradative autophagy selectively regulates CCND1 (cyclin D1) and MIR224, two oncogenic factors involved in hepatocellular carcinoma tumorigenesis. Autophagy 2019; 15: 729-730