The differences in immune features and genomic profiling between squamous cell carcinoma and adenocarcinoma - A multi-center study in Chinese patients with uterine cervical cancer.

BACKGROUND: Squamous cell carcinoma (SCC) and adenocarcinoma (AC) of the uterine cervix have distinct biological behaviors and different treatment responses. Studies on immune features and genomic profiling of these two pathologic types were limited and mainly focused on small patient cohorts. METHODS: From 2014 to 2021, 336 (254 SCC vs. 82 AC) cervical cancer patients who were diagnosed/treated in 7 medical centers in China were enrolled in the study. Next-generation sequencing of 425 cancer-relevant genes was performed on tumor tissues and liquid biopsies. Somatic alterations and immune response-related biomarkers were analyzed. Patient prognosis and immune infiltration were analyzed using data from The Cancer Genome Atlas (TCGA). RESULTS: AC tended to have more immunotherapy resistance-related STK11 alterations (P = 0.039), a higher proportion of microsatellite instability (P = 0.21), and more actionable mutations (P = 0.161). In contrast, higher tumor mutational burdens (TMB; P = 0.01), a higher proportion of TMB-high patients (P = 0.016), and more PD-L1-high patients (P = 0.0013) were observed in SCC. Multiple genetic alterations and aberrant signaling pathways were specifically enriched in AC (e.g., TP53, KRAS, ERBB2, and ARID1A alterations) or SCC (e.g., PIK3CA, FBXW7, EP300, and BAP1 mutations). Notably, AC-enriched genetic changes were significantly associated with decreased infiltrations of various B cells, T cells, and dendritic cells, whereas SCC-associated molecular features tended to be associated with increased CD4+ T cell infiltrations. CONCLUSIONS: This was the first multi-center study revealing the immunologic and genomic features between SCC and AC in Chinese patients with cervical cancer. Our findings have illustrated the difference in genetic profiles of those two cervical cancer subtypes, which may suggest the possibility of differential treatment regimens, with better immunotherapy efficacy in SCC and targeted therapy options more favorable in AC.

miR-16-5p modulates the radiosensitivity of cervical cancer cells via regulating coactivator-associated arginine methyltransferase 1.

This study was to investigate the expression of coactivator-associated arginine methyltransferase 1 (CARM1) and miR-16-5p in cervical cancer (CC), and explore their roles in radioresistance. Western blot and immunohistochemistry were used to detect the expression of CARM1 in tissues and cells. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the expression of miR-16-5p. CC cells received different doses of X-ray exposure, and then cell counting kit-8 method and colony formation assay were used to detect cell proliferation. Apoptosis was detected by flow cytometry. Then we used Targetscan database to predict that CARM1 is a potential target of miR-16-5p, and further verified the targeting relationship between them by western blot, RT-PCR and dual luciferase reporter experiments. We demonstrated that CARM1 were highly expressed in CC tissues and radio-resistant CC cells, while miR-16-5p expression was low. Under irradiation, up-regulation of CARM1 can induce radiotherapy resistance of CC cells, while overexpression of miR-16-5p or CARM1 knockdown could inhibit the survival of CC cell and induced apoptosis. CARM1 was verified as a target for miR-16-5p. Besides, up-regulation of CARM1 reversed the increase in radiosensitivity induced by miR-16-5p. Collectively, we concluded that miR-16-5p promoted the radiosensitivity of CC cells by targeting CARM1.

miR-122-5p modulates the radiosensitivity of cervical cancer cells by regulating cell division cycle 25A (CDC25A).

Cervical cancer is one of the most common gynecological malignancies globally, Unfortunately, radiotherapy and chemotherapy are not effective at treating some cases of this disease, and the 5-year survival rate is only 40-50%. Cell division cycle 25A (CDC25A) has been shown to induce radioresistance in a variety of tumor cells, but the role of CDC25A in the radioresistance of cervical cancer has not been fully elucidated. Here, we report that CDC25A is highly expressed and miR-122-5p lowly expressed in cervical cancer tissues and cells. The TargetScan database was used to predict CDC25A as a target of miR-122-5p, and the interactions between miR-122-5p and CDC25A were further confirmed by western blot, real-time PCR and dual-luciferase reporter assay. Under X-ray irradiation, up-regulation of CDC25A can promote the radiation resistance of cervical cancer cells, whereas overexpression of miR-122-5p or knockdown of CDC25A inhibits the survival and induces apoptosis of cervical cancer colonies. In conclusion, our data suggest that miR-122-5p enhances the radiosensitivity of cervical cancer cells by targeting CDC25A.