Quantitative ratio of mRNA expression of IGF/INS system receptors in multiple myeloma

Background. Individuals with increased expression of components of the IGF/INS system, are more likely to develop various malignancies. And in the case when the components of the IGF/INS system are overexpressed in tumors, this adversely affects the prognosis of the disease, including leading to a decrease in relapse-free survival. A characteristic feature of the IGF/INS system is the ability of the same ligands to bind to different receptors and vice versa (cross interactions) and activate different signaling pathways in the cell. This feature of the system requires an integrated approach to the study of the expression of its components, namely, the study of the quantitative ratio of the expression of individual components. The result obtained will make it possible to determine possible combinations of ligand-receptor bonds and, ultimately, will have both prognostic and evaluative value: in terms of a therapeutic target.

Aim. To establish the quantitative ratio of mRNA expression of the IGF/INS system receptors: IR-A, IR-B, IGF-1R, and IGF-2R in the IM9 lymphoblastoid cell line and in three myeloma cell lines: RPMI1640, RPMI8226, H929, and to identify frequency of expression of these receptors in the mononuclear fraction of bone marrow aspirates obtained from treated patients with multiple myeloma.

Materials and methods. We used human lymphoblastoid cells and 3 types of human myeloma cells, differing in the degree of differentiation and, as well as bone marrow aspirates obtained from 19 treated patients with stage III multiple myeloma. Expression of mRNA in cells was studied by quantitative real-time reverse transcription polymerase chain reaction and in bone marrow aspirate samples by semi-quantitative reverse transcription polymerase chain reaction.

Results. During the study, we found that within each cell line, the receptor IR-A is predominant compared to the receptor IR-B. Patients with MM have a high frequency of IR-A expression compared to IR-B. The minimum ratio of IGF-1R:IR-A and IGF-1R:IR-B mRNA is in IM9 lymphoblastoid cells, and for myeloma cells these ratios are high. The ratio of IGF-2R:IR-A is maximum for IM9 lymphoblastoid cells, and for myeloma cells this ratio is three or more times less.

Conclusion. Based on the study of the quantitative ratio of receptor mRNA, we state that in myeloma cells there is a high probability of the presence of IGF-1R/IGF-1R and IR-A/IR-A homodimers, and an IGF-1R/IR-A heterodimer. These data have both prognostic and evaluative value, since these combinations of receptors suggest a significant increase in the mitogenic effect due to activation by three ligands: IGF-1, IGF-2 and INS, which is an unfavorable factor, especially when a patient with multiple myeloma with concomitant Diabetes mellitus was prescribed insulin therapy along with chemotherapy. Based on our findings, we recommend simultaneously inhibiting both the IGF-1R receptor and the IR-A receptor as a therapeutic target.

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