CC BY
0South Russian Journal of Cancer. 2024. Vol. 5, No. 1. P. 17-24 https://doi.org/10.37748/2686-9039-2024-5-1-2 https://elibrary.ru/inmjlz
ORIGINAL ARTICLE
MicroRNA-34, microRNA-130, microRNA-148, microRNA-181, microRNA-194 and microRNA-605 expression in colon
cancer tissue
D. I. Azovsky1, S. G. Afanasyev1, A. V. Avgustinovich1, L. V. Spirina1,212, I. V. Kovaleva1,2,
A. B. Zinnurova2, V. A. Belova2
1 Cancer Research Institute - branch of the Federal State Budgetary Scientific Institution "Tomsk National Research Medical Center of the Russian Academy of Sciences", Tomsk, Russian Federation
2 Siberian State Medical University, Tomsk, Russian Federation
12 spirinalvl@mail.ru
Purpose of the study. Determination of the expression of microRNA-34, microRNA-130, microRNA-148, microRNA-181, mi- croRNA-194 and microRNA-605 in colon tumor tissue depending on the clinical and morphological features of the tumor and the effectiveness of treatment.
Materials and methods. The study included 56 patients diagnosed with colorectal cancer aged 43 to 75 years with the average age of 54 years. Taking into account the local prevalence of the process patients received surgical or combined treatment, including neoadjuvant chemotherapy, in the clinics of the Cancer Research Institute, Tomsk NRMC. MicroRNA expression was determined by polymerase chain reaction (PCR) in real time.
Results. The obtained information revealed the relation of microRNA-130 to the tumor size. The development of regional metastases was associated with changes in microRNA-130, microRNA-194 and microRNA-605. The level of histological or- ganization of the tumor was associated with microRNA-34, microRNA-130, microRNA-148, and the response to therapy - with microRNA-130, microRNA-148 and microRNA-605. In addition, according to the study, the significance of microRNA-130 was revealed, which is associated with tumor spread, histological differentiation and response to antitumor therapy.
Conclusion. The features of expression of microRNA-34, microRNA-130, microRNA-148, microRNA-181, microRNA-194 and microRNA-605 associated with clinical and morphological features of colon tumors were revealed. Correlations between the studied indicators are noted, which probably determine the outcome and prognosis of the disease.
For citation: Azovsky D. I., Afanasyev S. G., Augustinovich A. V., Spirina L. V., Kovaleva I. V., Zinnurova A. B., Belova V. A. MicroRNA-34, microRNA-130, microRNA-148, microRNA-181, microRNA-194 and microRNA-605 expression in colon cancer tissue. South Russian Journal of Cancer. 2024; 5(1): 17-24. https://doi.org/10.37748/2686-9039-2024-5-1-2, https://elibrary.ru/inmjlz
For correspondence: Liudmila V. Spirina - Dr. Sci. (Med.), Leading Researcher at the Laboratory of Tumor Biochemistry, Cancer Research Institute - branch of the Federal State Budgetary Scientific Institution "Tomsk National Research Medical Center of the Russian Academy of Sciences", Tomsk, Russian Federation; Head of the Department of Biochemistry and Molecular Biology with a course in clinical laboratory diagnostics, Siberian State Medical University, Tomsk, Russian Federation
Address: 5 Kooperativny str., Tomsk 634050, Russian Federation Address: 2 Moskovsky trakt, Tomsk 634050, Russian Federation E-mail: spirinalvl@mail.ru
ORCID: https://orcid.org/0000-0002-5269-736X SPIN: 1336-8363, AuthorID: 441893
ResearcherID: A-7760-2012 Scopus Author ID: 36960462500
Compliance with ethical standards: the ethical principles presented by the World Medical Association Declaration of Helsinki, 1964, ed. 2013 were observed in the study. The study was approved by the ethics committee of Cancer Research Institute, Tomsk NRMC (extract from the protocol of the meeting No. 22 dated 28/11/2022). Informed consent was received from all participants of the study
Funding: this work was not funded
Conflict of interest: the authors declare that there are no obvious and potential conflicts of interest associated with the publication of this article
The article was submitted 17.08.2023; approved after reviewing 22.01.2024; accepted for publication 27.02.2024
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12 spirinalvl@mail.ru
???? ????????????. ??????????? ?????????? ????????-34, ????????-130, ????????-148, ????????-181, ????????-194 ? ????????-605 ? ????? ??????? ????????? ????? ? ??????????? ?? ???????-??????????????? ???????????? ??????? ? ????????????? ???????.
????????? ? ??????. ? ???????????? ???? ???????? 56 ????????? ? ????????? ?????????????? ??? ? ??????- ?? ?? 43 ?? 75 ??? (??????? ??????? ???????? 54 ????). ???????? ???????? ????????????? ??? ??????????????? ???????, ??????? ?????????????? ???????????? ? ?????? ??????? ?????????????????? ????????, ? ???????? ??? ????????? ???????? ????. ?????????? ???????? ?????????? ??????? ???????????? ?????? ??????? (???) ? ???????? ???????.
??????????. ???????? ?????? ? ????? ????????-130 ? ???????? ???????. ???????? ??????????? ?????????? ???? ????????????? ? ?????????? ????????-130, ????????-194 ? ????????-605. ??????? ??????????????? ????- ??????? ??????? ??? ?????? ? ????????-34, ????????-130, ????????-148, ? ????? ?? ??????? - ? ????????-130, ????????-148 ? ????????-605. ????? ????, ?? ?????? ???????????? ???? ???????? ?????????? ????????-130, ??????? ??????? ? ???????????????? ???????, ??????????????? ???????????????? ? ??????? ?? ??????????????- ??? ???????.
??????????. ???????? ??????????? ?????????? ????????-34, ????????-130, ????????-148, ????????-181, ??- ??????-194 ? ????????-605, ??????????????? ? ???????-???????????????? ????????????? ??????? ????????? ?????. ???????? ?????????????? ??????????? ????? ???????????? ????????????, ???????, ????????, ?????????? ????? ? ??????? ???????????.
??? ???????????: ???????? ?. ?., ????????? ?. ?., ???????????? ?. ?., ??????? ?. ?., ???????? ?. ?., ????????? ?. ?., ?????? ?. ?. ?????????? ????????-34, ????????-130, ????????-148, ????????-181, ????????-194 ? ????????-605 ? ????? ??????? ????????? ?????. ????-?????????? ?????????????? ??????. 2024; 5(1): 17-24. https://doi.org/10.37748/2686-9039-2024-5-1-2, https://elibrary.ru/inmjlz
??? ???????????????: ??????? ??????? ?????????? - ?.?.?., ??????? ??????? ????????? ??????????? ???????? ????????, ??????- ????????????????? ???????? ????????? - ?????? ????? "??????? ???????????? ????????????????? ??????????? ????? ?????????? ???????? ????", ?. ?????, ?????????? ?????????; ?????????? ???????? ???????? ? ???????????? ???????? ? ?????? ??????????? ???????????? ???????????, ????? ?? "????????? ??????????????? ??????????? ???????????" ???????????? ??????????????? ?????????? ?????????,
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?????: 634050, ?????????? ?????????, ?. ?????, ???. ?????????????, ?. 5 ?????: 634050, ?????????? ?????????, ?.?????, ?????????? ?????, ?. 2
E-mail: spirinalvl@mail.ru
ORCID: https://orcid.org/0000-0002-5269-736X SPIN: 1336-8363, AuthorID: 441893
ResearcherID: A-7760-2012 Scopus Author ID: 36960462500
?????????? ????????? ??????????: ? ?????? ??????????? ????????? ????????, ????????????? ???????????? ??????????? ????????? ??????????? ?????????? (World Medical Association Declaration of Helsinki, 1964, ???. 2013). ???????????? ???????? ????????? ?? ?????????????? ????? ??? ??? ????????? ???????? ???? (??????? ?? ????????? ????????? ? 22 ?? 28.11.2022 ?.). ??????????????? ???????? ???????? ?? ???? ?????????? ????????????
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?????? ????????? ? ???????? 17.08.2023; ???????? ????? ?????????????? 22.01.2024; ??????? ? ?????????? 27.02.2024
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INTRODUCTION
Epigenetic regulation is a powerful factor deter- mining the molecular features of tumor growth and has a significant impact on the effectiveness of antitumor treatment [1]. Colon cancer ranks 6th in the world in terms of prevalence and 3rd among the most significant malignant tumors in the Russian Federation [2], which is associated with the activa- tion of significant signaling cascades.
Currently, the features of epigenetic regulation, particularly the importance of microRNAs, in the development of colon tumors have been little stud- ied [3]. It is believed that microRNA-34 and microR- NA-34a exhibit oncosuppressor properties, which is associated with the effect on the p53 protein and on the state of intracellular signaling cascades (IL-6R/ STAT3 and PI3K/AKT/mTOR) [4, 5]. Recent studies have shown that representatives of the microR- NA-148/152 family become attractive biomarkers to predict the biological behavior of tumors of vari- ous origins [6].
Another significant indicator is microRNA-194, which determines the features of oncogenesis in colorectal cancer [7, 8]. This fact is related to the regulatory effect of microRNA-194 on the activity of the MAP4K4/c-Jun/MDM2 signaling cascade, where it manifests itself as an oncosuppressor [3].
It is known that activation of the proteasome system accompanies the development of colon tu- mors [9]. microRNA-605 has been shown to be able to influence PSMD10, the ATP-independent subunit of proteasomes or gankyrin, determining, among other things, the risk of liver metastases [10].
There is practically no information about the role of microRNAs 130 and 181 in the development of colon cancer. It is known that high expression of the miRNA-130 family can predict an unfavorable prog- nosis in cancer patients [11]. Reduced expression of microRNA-130-5p in lung cancer tissues and cells contributed to the metastasis and invasion of this tu- mor due to EZH2 (Enhancer of zeste homolog 2) [12]. Recent studies have shown that representatives of the microRNA-181 family regulate significant in- tracellular processes: in cell proliferation, apoptosis, autophagy, angiogenesis, and drug resistance. In ad- dition, it has been demonstrated that the presented microRNAs exhibit their regulatory effects by mod- ulating a variety of signaling pathways, including
the PI3K/AKT, intracellular signaling pathway MAPK (MAPK), transforming growth factor beta (TGF-b), in- tracellular signaling pathway Wnt (Wnt), transcription factor ?B (NF-?B), intracellular signaling pathway Notch (Notch) [13].
Currently, a panel of microRNAs is known, includ- ing more than 10 microRNAs, including microRNA-34 and microRNA-148, which are associated with the development of resistance to antitumor drugs [14], but its diagnostic value is practically unknown.
The purpose of the study was to determine the dependence of the clinical and morphological fea- tures of the tumor and the effectiveness of treatment on the expression of microRNA-34, microRNA-130, microRNA-148, microRNA-181, microRNA-194 and microRNA-605 in colon tumor tissue.
MATERIALS AND METHODS
The study included 56 patients diagnosed with colorectal cancer aged 43 to 75 years (the average age was 54 years). The patients received combined treatment, including neoadjuvant chemotherapy at the clinics of the Cancer Research Institute, Tomsk NRMC. Treatment was carried out according to the following scheme: 8 courses of neoadjuvant poly- chemotherapy according to the FolFox-6 scheme, including administration on the first day: oxalipla- tin 85 mg/m2 2-hour infusion, calcium folinate 400 mg/m2 IV for 2 hours followed by a bolus of 5-flu- orouracil 400 mg/m2 IV jet and 46-an hour infusion of 5-fluorouracil 2400 mg/m2 (1200 mg/m2 / day) with an interval between courses of 14 days. Eighteen patients had the disease stage T2, 14 patients - T3 and 24 people - T4. The presence of regional metas- tases (N1-2) was recorded in 26 patients. Low grade tumors were detected in 44 patients, high grade in 12 patients. Partial regression of the tumor was not- ed in 46 patients and stabilization in 10.
The conduct of this work was approved by the
Ethical Committee of the Cancer Research Institute, Tomsk NRMC. All procedures involving patients were carried out in accordance with the Protocol of the Helsinki Declaration on Human Rights (1964), Pro- tocol No. 22 of 11/28/2022.
The research material was samples of the central part of the tumor and unchanged colon tissue ob- tained during surgical treatment, which were stored at a temperature of -80 �C.
Isolation of microRNAs
microRNA isolation was performed using a kit for isolation of total RNA and microRNA from the Lyra reagent (Biolabmix, Russia), combining meth- ods of phenol-chloroform extraction of nucleic acids and their selective sorption on a silicon membrane, where lysis of the sample occurs in the Lyra reagent containing phenol and guanidine thiocyanate. The quality and integrity of the isolated nucleic acids were evaluated using capillary electrophoresis on a TapeStation device (Agilient Technologies, USA). The RIN ranged from 2.2-3.3.
MicroRNA reverse transcription was performed using a set of reagents from M-MuLV-RH. The se- lected set represents a complete system for the effective synthesis of the first chain of cDNA with mRNA or total RNA matrices (Biolabmix, Russia).
Quantitative polymerase chain reaction (PCR)
with real-time reverse transcription
The level of gene expression was assessed us- ing quantitative real-time reverse transcriptase PCR (RT-qPCR) on an iCycler amplifier (DTprime, DNA technology, Russia). To obtain cDNA on an RNA ma- trix, a reverse transcription reaction was performed using the OT m-MuLV-RH kit (Biolabmix, Russia) with random hexanucleotide primers in accordance with the instructions for the kit. PCR was performed in three replicas with volumes of 25 �l, containing
12.5 �l of HS-qPCR SYBR Blue BioMaster (Biolabmix, Russia), 300 nM of direct, reverse and RT primers and 50 ng of cDNA. PCR primers: Hsa-miR-34a-5p: F: 5'-CGCGTGGCAGTGTCTTAGCT-3';
R: 5'-AGTGCAGGGTCCGAGGTATT-3';
RT Primer: 5'-GTCGTATCCAGTGCAGGGTCCGAG GTATTCGCAC TGGATACGACACAACC-3;
Hsa-mir-130a: F: 5'- GCCGCCAGTGCAATGTTAAA-3'; R: 5'- GTGCAGGGTCGGAGGT -3';
RT primer: 5'-GTCGTATCCAGTGCAGGGTCCGAGG- TATTCGCACTGGATACGACATGCCCT-3';
miR-148a-3p: F: 5'-TGCGCTCAGTGCACTACAGAAC-3'; R: 5'- CCAGTGCAGGGTCCGAGGTATT-3';
miR-181a: F: 5'- CGAACATTCAACGCTGTCG; R: 5'- AGTGCAGGGTCCGAGGTATT-3';
RT primer: 5'-AACATTCAACGCTGTCGGTGAGTGTC- GTATCCAG TGCGAATACCTCGGACCCTGCACTGGA- TACGAC-3';
Hsa-mir-194 F: 5'-CACGCATGTAACAGCAAC-3'; R: 5'-CCAGTGCAGGGTCCGAGGTA-3';
RT-primer: 5`-GTCGTATCGAGAGCAGGGTCCGAGG- TATT CGCACTCGATACGACTC CACAT-3`;
Hsa-mir-605: F: 5'-TGCGGTAAATCCCATGGTG- CCTTC-3';
R: 5'-CCAGTGCAGGGTCCGAGGT-3';
RT: 5'-GTCGTATCCAGTGCAGGGTCCGAGGTGCACT- GGATACGACAGGAGAAG-3';
U6: F 5'-CTCGCTT CGGCAGCACATATACT-3', R 5'-ACGCTTCACGAATTTGCGTGTC-3',
RT primer 5'-AAAATATGGAACGCTTC ACGAATTTGG-3.
Real-time PCR
The two-step amplification program included 1 cycle of 94 �C, 10 minutes of pre-denaturation;
40 cycles of 1st step 94 �C, 10 seconds and 2 step 20 seconds - at a temperature of 60 �C. To quantify the level of microRNA expression, the method of rel- ative determination of quantitative values of 2-??Ct was used. The expression of small nuclear RNU6 RNA was used as an endogenous control.
Statistical processing of the results was carried out using the Statistica 12.0 software package. Data validation for the normality of the distribution was performed using the Kolmogorov-Smirnov criterion. The values of gene expression are presented in con- ventional units of expression (relative units) as Me (Q1; Q3). The Mann-Whitney test was used to assess significant differences. The differences were consid- ered significant at p < 0.05. Spearman's criterion was used in the correlation analysis.
STUDY RESULTS
It was revealed that the expression of microR- NA-130 increased with increasing depth of invasion of the primary tumor (Table 1). At the same time, the appearance of regional metastases was associated with an increase in the expression of microRNA-130 by 1.9 times, while a decrease in the degree of tumor differentiation was accompanied by a decrease in the expression of this indicator. An increase of this indicator was recorded by 28.2 times with stabiliza- tion of the tumor process compared with patients with partial regression.
A similar picture with respect to the invasive po- tential of the tumor was obtained for microRNA-148, whose expression increased with a decrease in the degree of differentiation, as well as with a decrease in the tumor response to treatment in patients with
stabilization of the process, a 9.3-fold lower level of expression was noted compared with patients who achieved partial regression.
The opposite data were obtained for microR- NA-194, which decreased by 3.2 times in the case of regional metastases. At the same time, an increase in the expression of the indicator was combined with a decrease in the degree of histological organization of the tumor and with a decrease in the effect of the tumor on treatment. This indicator was reduced by
7.2 times.
The expression of microRNA-605 in the tumor was
2.0 times higher in the presence of regional metasta- ses compared with localized tumor variants. At the same time, in the case of highly differentiated tumors, the lowest indicators were noted, and in high grade car- cinoma, the expression of the indicator was increased by 12.1 times compared with the above-described pa- tients. An increase of 60.3 times was recorded for patients with a reduced response to therapy.
The association of histological differentiation of the tumor with microRNA expression was also con-
0.15
(0.00; 0.46)
0.03
(0.00; 0.93)
0.37
(0.00; 1.35)
0.06
(0.00; 0.11)$
0.33
(0.00; 0.93)$
0.94
(0.52; 4.77)$
0.53
(0.27; 0.93)
1.14
(0.38; 1.74)
1.28
(0.59; 2.30)
0.00
(0.00; 0.00)
0.00
(0.00; 0.00)
0.00
(0.00; 0.00)
0.47
(0.12; 0.66)
1.07
(0.00; 2.83)
0.73
(0.47; 1.43)
0.12
(0.00; 0.87)
2.46
(0.00; 2.83)
1.04
(0.39; 11.79)
0.35
(0.00; 0.71)
0.15
(0.00; 4.00)
0.43
(0.06; 1.74)
0.81
(0.11; 3.48)*
0.93
(0.27; 1.74)
1.15
(0.61; 2.00)
0.00
(0.00; 0.00)
0.00
(0.00; 0.00)
0.71
(0.27; 2.83)
0.22
(0.00; 0.43)*
0.87
(0.00; 21.11)
1.74
(0.19; 2. 64)*
0.44
(0.02; 1.35)
0.04
(0.00; 0.07) **
0.87
(0.47; 2.61)
3.25
(0.00; 6.50)**
1.37
(0.23; 1.78)
11.13
(1.14; 21.11)**
0.00
(0.00; 0.00)
0.00
(0.00; 0.00)
0.65
(0.00; 1.31)
6.73
(1.23; 12.23)**
0.87
(0.39; 17.41)$$$
10.56 (0.00;21.11)**
Local regression
0.09
(0.00; 0.62)
0.23
(0.03; 0.84)
0.97
(0.19; 1.28)
0.00
(0.00; 0.00)
0.68
(0.06; 0.99)
0.35
(0.00; 1.81)
Stabilisation 10 0.07
6.5
(0.50; 14.93)#
9.19
(2.14; 21.11)#
0.00
(0.00; 0.00)
4. 92
(0.00; 12.23)#
21.11
(0.20; 32.0)#
Note: * - significance of differences compared with patients without regional metastases, p < 0.05; ** - significance of differences compared with patients with low grade tumors, p < 0.05; # - significance of differences compared with patients with partial regression, p < 0.05;
$ - significance of differences according to the Kruskal criterion-Wallis, p < 0.05
firmed for microRNA-34, the expression of which was increased by 11.0 times in low-grade carcinoma tissue. As a result of the correlation analysis, positive associations were noted between the studied in- dicators (Table 2). However, no correlation depen- dencies were found between microRNA-34 and mi-
croRNA-148.
DISCUSSION
During the study, data on the microRNA-130 link to the depth of tumor invasion were noted. There is evidence of the relationship of this indicator with the prognosis of the disease in cancer patients [11]. The development of regional metastases was as- sociated with changes in microRNA-130, microR- NA-194 and microRNA-605. At the same time, tumor aggressiveness was associated with low expression of microRNA-194, which is associated with activation of the MAP4K4/c-Jun/MDM2 sig- naling chain [3].
The level of histological organization of the tumor was associated with microRNA-34, microRNA-130, microRNA-148, and the response to therapy with microRNA-130, microRNA-148 and microRNA-605. microRNA-34 is believed to be an oncosuppres-
sor [15, 16], therefore, the low level of the indica- tor was associated with high grade carcinomas. It is known that microRNA-148 is a universal marker of the biological behavior of tumors of various ori- gins [6], and microRNA-605 can modify the PSMD10 protein, gankyrin, and participate in the formation of invasive tumor potential [10].
Despite the importance of the miR-181 family in controlling of cell proliferation, apoptosis, autopha- gy, angiogenesis, and drug resistance [16, 17], mi- croRNA-181 expression was not detected in tumor tissue. There were also no correlations between mi- croRNA-34 and microRNA-148 included in the model for predicting the effectiveness of antitumor treat- ment [18, 19]. The information received probably requires further study.
In addition, according to the study, the significance of microRNA-130 was revealed, which is associated with tumor spread, histological differentiation and response to antitumor therapy [20, 21]. Consequently, the importance of epigenetic regulation in the de- velopment of malignant neoplasms is associated with their involvement in the activation of significant signaling cascades, for example, PI3K/AKT, MAPK, TGF-b, Wnt, NF-?B, Notch [21], as well as growth and transcription factors [22].
Table 2. Analysis of link between the expression of microRNA-34, microRNA-130, microRNA-148, microRNA-181, microRNA-194 and microRNA-605 in colon tumor tissue Spearman's Coefficient, R t(N-2) p MicroRNA-34 & MicroRNA -130 0.493 4.169 0.001 MicroRNA ?-34 & MicroRNA -148 0.162 1.207 0.232 MicroRNA -34 & MicroRNA -194 0.359 2.828 0.006 MicroRNA -34 & MicroRNA -605 0.495 4.189 0.001 MicroRNA -130 & MicroRNA-148 0.547 4.805 0.003 MicroRNA -130 & MicroRNA -194 0.409 3.298 0.001 MicroRNA -130 & MicroRNA -605 0.688 6.975 0.000 MicroRNA -148 & MicroRNA -194 0.640 6.134 0.000 MicroRNA -148 & MicroRNA -605 0.540 4.725 0.000 MicroRNA -194 & MicroRNA -605 0.458 3.788 0.003 Notes: ? - the significance of the differences
CONCLUSION
Thus, epigenetic regulation is important in the development of malignant neoplasms. The ex- pression features of microRNA-34, microRNA-130, microRNA-148, microRNA-181, microRNA-194 and microRNA-605 links to the clinical and morpho-
logical features of colon tumors were revealed. microRNA-130 is a promising indicator that deter- mines tumor development and response to treat- ment. The absence of microRNA-181 in colon cancer tissue has been shown, which undoubtedly requires further study. There was an increase in the expres- sion of microRNA-34 in low grade tumors.
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Information about authors:
Daniil I. Azovsky - MD, oncologist physician at the Abdominal Oncology Department, Cancer Research Institute - branch of the Federal State Budgetary Scientific Institution "Tomsk National Research Medical Center of the Russian Academy of Sciences", Tomsk, Russian Federation ORCID: https://orcid.org/0000-0001-7375-9585, SPIN: 1540-2016, AuthorID: 1059659
Sergei G. Afanasyev - Dr. Sci. (Med.), professor, Head of the Abdominal Oncology Department, Cancer Research Institute - branch of the Federal State Budgetary Scientific Institution "Tomsk National Research Medical Center of the Russian Academy of Sciences", Tomsk, Russian Federation ORCID: https://orcid.org/0000-0002-4701-0375, SPIN: 9206-3037, AuthorID: 264236, ResearcherID: D-2084-2012, Scopus Author ID: 21333316900
Alexandra V. Avgustinovich - Cand. Sci. (Med.), Senior Researcher at the Department of Abdominal Oncology, Cancer Research Institute - branch of the Federal State Budgetary Scientific Institution "Tomsk National Research Medical Center of the Russian Academy of Sciences", Tomsk, Russian Federation
ORCID: https://orcid.org/0000-0003-3796-7218, SPIN-2952-6119, AuthorID: 558788
Liudmila V. Spirina 12 - Dr. Sci. (Med.), Leading Researcher at the Laboratory of Tumor Biochemistry, Cancer Research Institute - branch of the Federal State Budgetary Scientific Institution "Tomsk National Research Medical Center of the Russian Academy of Sciences", Tomsk, Russian Federation; Head of the Department of Biochemistry and Molecular Biology with a course in clinical laboratory diagnostics, Siberian State Medical University, Tomsk, Russian Federation
ORCID: https://orcid.org/0000-0002-5269-736X, SPIN: 1336-8363, AuthorID: 441893, ResearcherID: A-7760-2012, Scopus Author ID: 36960462500
Irina V. Kovaleva - laboratory assistant-researcher at the Laboratory of Tumor Biochemistry, Cancer Research Institute - branch of the Federal State Budgetary Scientific Institution "Tomsk National Research Medical Center of the Russian Academy of Sciences", Tomsk, Russian Federation; Assistant at the Department of Biochemistry and Molecular Biology with a course in clinical laboratory diagnostics, Siberian State Medical University, Tomsk, Russian Federation
ORCID: https://orcid.org/0000-0003-2964-9041, SPIN: 9737-7086, AuthorID: 1076520, Scopus Author ID: 57215197522
Alina B. Zinnurova - student, Siberian State Medical University, Tomsk, Russian Federation. ORCID: https://orcid.org/0009-0006-1126-5890
Victoria A. Belova - student, Siberian State Medical University, Tomsk, Russian Federation. ORCID: https://orcid.org/0009-0007-9820-9636, AuthorID: 600452
Contribution of the authors:
Azovsky D. I. - analysis of the results;
Afanasyev S. G. - formulation of the purpose of the study; Augustinovich A. V. - scientific editing; clinical support of the study; Spirina L. V. - writing an article;
Kovaleva I. V. - research design;
Zinnurova A. B. - formation of patient groups; Belova V. A. - participation in the study.
