Tae Oike

Objective: Endometrial cancer (EC) is one of the most common cancers in women, and its incidence is increasing worldwide. The prognosis of recurrent and advanced cancer remains poor because treatment options are limited. Ubiquitin C-terminal hydrolase-L1 (UCHL1) is associated with the progression of several cancers including EC. In this study, we analyzed the function of UCHL1 in EC progression. Methods: UCHL1 expression in the serum of patients with EC was measured using an enzyme-linked immunosorbent assay. Changes in cell migration and invasion were analyzed in UCHL1-overexpressing or UCHL1-knockdown cells (UCHL1-OE/UCHL1-KD) using wound-healing and transwell assays. Messenger RNA expression of epithelial–mesenchymal transition (EMT)-related genes in each cell was detected using quantitative real-time polymerase chain reaction (qRT-PCR). UCHL1 and EMT marker proteins were detected with Western blotting and an immunofluorescence assay (IFA). Results: Serum UCHL1 expression was significantly elevated in patients with metastases. Wound-healing assays and transwell assays showed that UCHL1 could promote cell migration and invasion. These effects were suppressed by UCHL1 knockdown and inhibition. UCHL1 overexpression modulated the expressions of EMT-related molecules in EC cells at the mRNA and protein levels. Furthermore, IFA analysis showed that changes in EMT-related molecules were consistent with lesions of UCHL1 expression. Conclusions: This study revealed that UCHL1 could contribute to promoting cell migration and invasion. These results may be associated with EMT regulation in EC cells.

Radiotherapy is a definitive treatment for early-stage cervical cancer; however, a subset of this disease recurs locally, necessitating establishment of predictive biomarkers and treatment strategies. To address this issue, we performed gene panel-based sequencing of 18 stage IB cervical cancers treated with definitive radiotherapy, including two cases of local recurrence, followed by in vitro and in silico analyses. Simultaneous mutations in KRAS and SMAD4 (KRAS^mt/SMAD4^mt) were detected only in a local recurrence case, indicating potential association of this mutation signature with radioresistance. In isogenic cell-based experiments, a combination of activating KRAS mutation and SMAD4 deficiency led to X-ray resistance, whereas either of these factors alone did not. Analysis of genomic data from 55,308 cancers showed a significant trend toward co-occurrence of mutations in KRAS and SMAD4. Gene Set Enrichment Analysis of the Cancer Cell Line Encyclopedia dataset suggested upregulation of the pathways involved in epithelial mesenchymal transition and inflammatory responses in KRAS^mt/SMAD4^mt cancer cells. Notably, irradiation with therapeutic carbon ions led to robust killing of X-ray-resistant KRAS^mt/SMAD4^mt cancer cells. These data indicate that the KRAS^mt/SMAD4^mt signature is a potential predictor of radioresistance, and that carbon ion radiotherapy is a potential option to treat early-stage cervical cancers with the KRAS^mt/SMAD4^mt signature.

The elevation of the serum squamous cell carcinoma (SCC) antigen unrelated to disease progression occurs during the follow-up of patients with cervical cancer treated with radiotherapy. Although known empirically, the incidence and characteristics of this non-cancer specific elevation in SCC remain unclear. Here, we examined the post-treatment kinetics of SCC in 143 consecutive patients with squamous cell carcinoma of the cervix treated with definitive radiotherapy; in all patients, progression-free disease status was confirmed by periodic monitoring for at least 36 months (median, 61 months). We found that the 5-year cumulative incidence of post-treatment SCC elevation was unexpectedly high at 37.3% (59/143 patients), and that 59.3% (35/59) of event-positive patients experienced multiple events. The median peak SCC level for a given event was 2.0 ng/mL (interquartile range, 1.7–2.9 ng/mL). The multivariate analysis showed that renal dysfunction was associated significantly with a greater incidence of SCC elevation (p = 0.046). In addition, the 5-year cumulative incidence of SCC elevation was significantly greater in patients with renal dysfunction than in those without (54.8% vs. 32.9%, respectively; hazard ratio, 2.1 [95% confidence interval, 1.1–4.2]; p = 0.028). These data will be useful for monitoring cervical cancer patients treated with radiotherapy.