ABSTRACT
Cervical cancer is a public health problem diagnosed in advanced stages, and its main risk factor is persistent high-risk human papillomavirus infection. Today, it is necessary to study new treatment strategies, such as immunotherapy, that use different targets of the tumor microenvironment. In this study, the K14E7E2 mouse was used as a cervical cancer model to evaluate the inhibition of indolamine-2,3-dioxygenase 1 (IDO-1) and C-X-C chemokine receptor type 2 (CXCR-2) as potential anti-tumor targets. DL-1MT and SB225002 were administered for 30 days in two regimens (R1 and R2) based on combination and single therapy approaches to inhibit IDO-1 and CXCR-2, respectively. Subsequently, the reproductive tracts were resected and analyzed to determine the tumor areas, and IHCs were performed to assess proliferation, apoptosis, and CD8 cellular infiltration. Our results revealed that combined inhibition of IDO-1 and CXCR-2 significantly reduces the areas of cervical tumors (from 196.0 mm2 to 58.24 mm2 in R1 and 149.6 mm2 to 52.65 mm2 in R2), accompanied by regions of moderate dysplasia, decreased papillae, and reduced inflammation. Furthermore, the proliferation diminished, and apoptosis and intra-tumoral CD8 T cells increased. In conclusion, the combined inhibition of IDO-1 and CXCR-2 is helpful in the antitumor response against preclinical cervical cancer.
ABSTRACT
Circulating biological markers, such as miRNAs, hold the greatest possibilities to complement tissue biopsy and clinical diagnostic tests. The objective of this study was to evaluate the relative abundance of three circulating miRNAs in serum from 17 HPV16-positive patients with early cervical lesions known as Low-Grade Squamous Intraepithelial Lesions (LSILs). The expression of circulating microRNAs miR-15b, miR-34a and miR-218 in patients with LSILs was compared to 23 HPV-negative individuals showing normal cervical epithelium (healthy women) and 23 Squamous Cell Carcinoma (SCC) samples. The expression levels of miR-15b remained unchanged while those of miRNAs 34a and 218 were relatively high in serum obtained from LSIL patients in comparison with healthy women (results were statistically significant with a p of < 0.01 or < 0.001). According to previous findings, miR-15b was overexpressed and miRNAs 34a and 218 were underexpressed in serum from SCC patients. Additionally, the mRNA expression levels of some selected gene targets were determined [Cyclin D1 (CCND1), Cyclin E1 (CCNE1), B-cell lymphoma 2 (Bcl-2) and MutS homolog 2 (MSH-2)]. All serum results correlated with tissue samples from the same patients. We propose that circulating microRNAs can be valuable as molecular markers for the early follow-up of cervical carcinogenesis risk.
