Molecular aspects of predicting recurrence of retroperitoneal extraorgan liposarcomas

Purpose of the study. The aim of the work was to optimize the prognosis of recurrences of retroperitoneal extraorgan liposarcomas of various degrees of differentiation by detecting microRNAs (miRNAs) of tumor cells with differential expression depending on the course of the malignant disease.

Materials and methods. The study was conducted on 96 patients: 19 patients with lipomas and 77 patients with retroperitoneal extraorgan liposarcomas. Tissue samples were obtained during the operation. Among patients with malignant diseases, highly differentiated liposarcoma (VDLS) was detected in 51 patients, and dedifferentiated (DDLS) in 26 patients. miRNA expression levels in tumor cells were determined using real-time PCR.

Results. During the follow-up period, relapses of malignant disease were detected in 25 (32,5%) people: 13 (25,5%) among patients with VDLS and 12 (46,2%) among patients with DDLS. In DDLS, characterized by a more aggressive course, there was an increased level of expression of miRNA155, -21, -26a2 and a decrease in expression of miRNA15a and -34 compared with patients with VDLS. In patients with recurrent retroperitoneal liposarcomas, the expression of miRNA15a was initially 83% lower in tumor cells of surgical samples (p<0,001), iRNA34 by 79% (p< 0,001), and the expression activity of miRNA155 was 7,54 times higher (p<0,001) and miRNA26a2 by 6,93 times (p<0,001).

Conclusion. The determination of the expression of miRNA155, -26a2, -34, -15a in tumor cells during surgical treatment of patients with retroperitoneal liposarcomas is an effective way to assess the risk of recurrence and is relevant for determining the tactics of further treatment of patients.

1. Kit O.I., Ausheva T.V., Maksimov A. Yu., Demidova A.A., Alikhanova S.S., Shulga A.A. et al. Influence of age, gender and histologic characteristics on the long-term survival of patients with soft tissue sarcomas. Sovremennye problemy nauki i obrazovaniya (Modern problems of science and education). 2024; 3: URL: https://science-education.ru/ru/article/view?id=33409 (In Russ.)

2. Gamboa A.C., Gronchi A., Cardona K. Soft-tissue sarcoma in adults: An update on the current state of histiotype-specific management in an era of personalized medicine. CA Cancer J. Clin. 2020; 70: 200–229. DOI: 10.3322/caac.21605

3. Wang J., Grignol V.P., Gronchi A., Luo C.-H., Pollock R.E., Tseng W.W. Surgical management of retroperitoneal sarcoma and opportunities for global collaboration. Chin. Clin. Oncol. 2018; 7: 39. DOI: 10.21037/cco.2018.07.05

4. Bill K.L.J., Casadei L., Prudner B.C., Iwenofu H., Strohecker A.M., Pollock R.E. Liposarcoma: Molecular targets and therapeutic implications. Cell. Mol. Life Sci. 2016; 73: 3711–3718. DOI: 10.1007/s0001801622662

5. Omelchenko D.V., Vasin A.B. Patients with Primary Malignant Retroperitoneal Tumor: Surgical Treatment Outcomes. Kreativnaya hirurgiya i onkologiya (Creative surgery and oncology). 2023; 13(1): 45–50. (In Russ.). DOI: 10.24060/2076-3093-2023-13-1-45-50

6. Volkov A. Yu., Nered S.N., Lyubchenko L.N. Retroperitoneal non-organ liposarcomas: the modern concept. Sibirskij onkologicheskij zhurnal (Siberian journal of oncology). 2019; 18 (5): 86–96. (In Russ.). DOI: 10.21294/1814-4861-2019-18-5-86-96

7. Sun R., Shen J.K., Choy E., Yu Z., Hornicek F.J., Duan Z. The emerging roles and therapeutic potential of microRNAs (miRs) in liposarcoma. Discov Med. 2015; 20: 311–324.

8. Latham G.J. Normalization of microRNA quantitative RT-PCR data in reduced scale experimental designs. Methods Mol Biol. 2010; 667: 19–31. DOI: 10.1007/9781607618119_2

9. Neville M.J., Collins J.M., Gloyn A.L., McCarthy M.I., Karpe F. Comprehensive human adipose tissue mRNA and microRNA endogenous control selection for quantitative real-time-PCR normalization. Obesity (Silver Spring). 2011; 19: 888–892. DOI: 10.1038/oby.2010.257

10. Li J., Smyth P., Flavin R., Cahill S., Denning K., Aherne S. et al. Comparison of miRNA expression patterns using total RNA extracted from matched samples of formalin-fixed paraffin-embedded (FFPE) cells and snap frozen cells. BMC Biotechnol. 2007; 7: 36. DOI: 10.1186/14726750736

11. Nana-Sinkam S.P., Croce C.M. Clinical applications for microRNAs in cancer. Clin. Pharmacol. Ther. 2013; 93: 98–104. DOI: 10.1038/clpt.2012.192

12. Braga E.A., Pronina I.V., Filippova E.A., Burdennyy A.M., Lukina S.S., Loginov V.I., Kushlinsky D.N. et al. Functional and clinical significance of miRNA genes group methylation and expression in tumors from patients with metastatic ovarian cancer. Klinicheskaya Laboratornaya Diagnostika (Clinical laboratory diagnostics). 2023; 68 (1): 56–64. (InRuss.) DOI: 10.51620/0869-2084-2023-68-1-56-64

13. Vincenzi B., Iuliani M., Zoccoli A., Pantano F., Fioramonti M., De Lisi D. et al. Deregulation of dicer and mir155 expression in liposarcoma. Oncotarget. 2015; 6: 10586–10591. DOI: 10.18632/oncotarget.3201

14. Nezu Y., Hagiwara K., Yamamoto Y., Fujiwara T., Matsuo K., Yoshida A. et al. miR135b, a key regulator of malignancy, is linked to poor prognosis in human myxoid liposarcoma. Oncogene. 2016 Dec 1; 35 (48): 6177–6188. DOI: 10.1038/onc.2016.157

15. Zhang P., Bill K., Liu J., Young E., Peng T., Bolshakov S. et al. MiR155 is a liposarcoma oncogene that targets casein kinase1alpha and enhances beta-catenin signaling. Cancer Res. 2012; 72: 1751–1762. DOI: 10.1158/0008–5472.CAN11–3027

16. Lee D.H., Forscher C., Di Vizio D., Koeffler H.P. Induction of p53-independent apoptosis by ectopic expression of HOXA5 in human liposarcomas. Sci. Rep. 2015; 5: 12580. DOI: 10.1038/srep12580

17. Wang R., Ma J., Wu Q., Xia J., Miele L., Sarkar F.H. et al. Functional role of miR34 family in human cancer. Curr Drug Targets. 2013; 14 (10): 1185–1191. DOI: 10.2174/13894501113149990191

18. Okada N., Lin C.P., Ribeiro M.C., Biton A., Lai G., He X. et al. A positive feedback between p53 and miR34 miRNAs mediates tumor suppression. Genes Dev. 2014; 28 (5): 438–450. DOI: 10.1101/gad.233585.113

19. Cimmino A., Calin G.A., Fabbri M., Iorio M.V., Ferracin M., Shimizu M. et al. miR15 and miR16 induce apoptosis by targeting BCL2. Proc. Natl. Acad. Sci. USA. 2005; 102 (39): 13944–13949. DOI: 10.1073/pnas.0506654102