Serum miR-638 Combined with Squamous Cell Carcinoma-Related Antigen as Potential Screening Biomarkers for Cervical Squamous Cell Carcinoma

Abstract

Aims: Cervical cancer is the second most common cause of cancer-related deaths in developing nations. Human papillomavirus prophylactic vaccines are not widely available, and there are shortages of gynecologists and cytologists in the already overburdened health care systems. The aim of this study was to identify circulating microRNAs (miRNAs) that could be used as feasible screening tests for cervical cancer in low-resource regions. Materials and Methods: Serum expression levels of five miRNAs were measured and validated by quantitative real-time polymerase chain reaction in cervical squamous cell carcinoma (CSCC) patients, cervical intraepithelial neoplasia patients, and healthy individuals. Squamous cell carcinoma-related antigen (SCC-Ag) was also measured in the serum. Results: Serum miR-638, miR-203a-3p, miR-1914-5p, and miR-521 levels were downregulated in the CSCC group (p < 0.05). Receiver operating characteristic (ROC) curve analysis indicated that the area under the ROC curve (AUC) values for miR-638 and miR-521 were 0.734 and 0.742, respectively, for discriminating CSCC patients from healthy controls. Furthermore, the combined use of miR-638 and SCC-Ag yielded the best screening performance and increased the AUC value, sensitivity, and specificity to 0.956, 94.87%, and 80.00%, respectively. Conclusion: This study suggested that miR-638 and miR-521 have independent screening value and that the combined measurement of miR-638 and SCC-Ag resulted in a better ability to discriminate patients with CSCC from healthy individuals.

Systematic review of circulating MICRORNAS as biomarkers of cervical carcinogenesis

“…Ten studies reported the tumor stage according to the International Federation of Gynecology and Obstetrics (FIGO) and 161 women were diagnosed with metastatic cervical cancer while 285 were not, but 11 studies did not report any information related to the presence of metastasis. Regarding the histological type, most studies diagnosed squamous cell carcinoma as the most prevalent: LIU; XIN; MA (carcinoma: 84, others: 21) [ 11 ], NAGAMITSU et al, (carcinoma: 38, adenocarcinoma: 06) [ 12 ], WEI; WEN-MING; JUN-BO (squamous cell carcinoma: 101, adenocarcinoma: 19) [ 15 ], YANG; ZHANG (epithelial cell carcinoma: 39, adenocarcinoma: 11) [ 19 ], ZHENG et al(epithelial cell carcinoma) [ 21 ], QIU et al (carcinoma: 107, adenocarcinoma: 05) [ 22 ], YAMANAKA et al (carcinoma: 37, adenocarcinoma: 09) [ 26 ]. Squamous cell carcinoma was the prevalent type in all CC women in Aftab et al [ 23 ] and Ocadiz-Delgado et al [ 25 ] studies.…”

“…Elevated AUC values were also observed for miR-9: 0.99; miR-192: 1 and miR-205: 0.96 [ 17 ], as well as for miR-638: 0.734; miR-203a-3p: 0.660; miR-1914-5p: 0.626 and miR-521: 0.742 [ 21 ] and miR-21: 0,783; miR-125b: 0,642 and miR-370: 0,822 [ 22 ]. When comparing patients in the CC and CIN groups, the following AUC values were obtained: miR-145: 0.828 [ 15 ]; miR-152: 0.831 [ 19 ]; miR-497, miR-16-2*, miR-195 and miR-2861 combined to form a panel: 0.829 [ 8 ]; miR-9: 0.85, miR-192: 0.82 and miR-205: 0.75 [ 17 ]; miR-638: 0.681, miR-203a-3p: 0.651, miR-1914-5p: 0.717 and miR-521: 0.716 [ 21 ]; miR-21: 0,689; miR-125b: 0,735 and miR-370: 0,821 [ 22 ]. The AUC value of 0.897 was obtained for miR-21, miR-125b e miR-370 when combined [ 22 ].…”

“…The description of the participant characteristics, such as age, type of lesion, tumor stage and presence of metastasis, whether the patients are undergoing chemotherapy are important to define whether the study findings can be generalized to show their possible limitations. The presence of HPV infection, for example, can also potentially alter the expression of circulating microRNAs [29] Table 4 Up and downregulated microRNAs expressed in patients with CIN and CC compared to healthy controls reported in the included studies * When comparing CIN and CC patients to healthy controls Upregulated miRNAs* Downregulated miRNAs* miR-196a [11] miR-195 e miR-2861 [8] miR-16-2* e miR-497 [8] miR-145 [15] miR-1290 [12] miRNA-214, −34a e -200a [18] miR-425-5p [13] let-7d-3p e miR-30d-5p [20] miR-92a [14] miR-638, miR-203a-3p, miR-1914-5p e miR-521 [21] miR-1266 [16] miR-125b and miR-370 [22] miR-9, miR-192 e miR-205 [17] miR-34a and miR-218 [25] miRNA-21 [18] miR-100 [26] miR-152 [19] miR-34a-5p, miR-145-5p and miR-218-5p [23] miR-21 [22] miR-15b, miR-34a and miR-218 [25] miR-21-5p, miR-199a-5p and miR-155-5p [23] Fig. 2 Quality assessment of studies using the Quality Assessment of Diagnostic Accuracy Studies 2 score system [30], which have been shown to play an important role in many physiological and pathological processes such as viral infections and oncogenesis.…”

“… Zheng et al [ 20 ] 2019 Digital PCR miR-128-3p miR-129-5p miR-320 let-7i-5p R_score N/I let-7d-3p miR-30d-5p No let-7d-3p: 0.822 miR-30d-5p: 0.79 Combined: 0.828 N/I N/I Let-7d-3p and miR-30d-5p expression levels were significantly decreased in CIN II + group when compared to CIN I – group. Zheng et al [ 21 ] 2020 qPCR cel-miR-39 2 −ΔΔCt N/I miR-638 miR-203a-3p miR-1914-5p miR-521 No CC vs. CIN miR-638: 0,681 miR-203a-3p: 0,651 miR-1914-5p: 0,717 miR-521: 0,716 CC vs. C miR-638: 0,734 miR-203a-3p: 0,660 miR-1914-5p: 0,626 miR-521: 0,742 CC vs. CIN miR-638: 85% miR-203a-3p: 42,5% miR-1914-5p: 82,5% miR-521: 62,5% CC vs. C miR-638: 80% miR-203a-3p: 75% miR-1914-5p: 85% miR-521: 80% CC vs. CIN miR-638: 46,15% miR-203a-3p: 82,05% miR-1914-5p: 61,54% miR-521: 76,92% CC vs. C miR-638: 60,98% miR-203a-3p: 53,66% miR-1914-5p: 43,90% miR-521: 65,85% Lower expression levels of miR-638, miR-203a-3p, miR-1914-5p and and MiR-521 were observed in the group compared to CIN. Furthermore, miR-638, miR-203a-3,p and miR-521 expression levels were lower in CC patients compared to healthy controls.…”

Circulating cervical cancer biomarkers potentially useful in medical attention (Review)

“…For CC, there are several studies showing biomolecules, proteins, non-coding RNAs (ncRNAs), and circulating DNA (cDNA) with a great potential to be useful biomarkers for diagnosis, prognosis, and to determine the response to treatments currently used in medical attention for CC. Although certain of these protein biomarkers may also function as biomarkers for other HPV-related cancers, previous studies showed that the combined use of these molecules increases their potential as biomarkers for this disease (6)(7)(8). Although these biomarkers have a sensitivity very similar to that of colposcopy and p16 (Table I) , a significant advantage is that it is a minimally invasive methodology, having a very important impact on the number of women who would be screened with this test.…”