Objective: Esophageal cancer is one of the deadliest cancers in the world, and the main subtype is esophageal squamous cell carcinoma (ESCC), which comprises 90% of cases. Expression of tryptophan 2,3-dioxygenase (TDO2), an enzyme involved in tryptophan catabolism, has been linked with tumor survival and poor prognosis of brain and breast cancer. However, no studies have investigated the potential role of TDO2 in esophageal cancer. Here we explored the expression and biological significance of TDO2 in ESCC. Methods: TDO2 protein expression was evaluated in 90 ESCC tissue samples by immunohistochemistry. TDO2 function in ESCC cell lines and spheroid colony formation were evaluated by RNA interference (RNAi). Results: TDO2 overexpression was associated with tumor stage, recurrence status, and the CD44 cancer stem cell marker in ESCC. TDO2 overexpression was correlated with poor outcome of ESCC patients. Inhibition of TDO2 expression by RNAi in TE-10 and TE-11 cell lines reduced both the number and the size of spheroid colonies as well as cell proliferation. Knockdown of TDO2 expression also induced inactivation of the epidermal growth factor receptor signaling pathway. Conclusion: Our results imply that TDO2 could play an important role in the progression of ESCC. Furthermore, TDO2 may be a potential therapeutic target in ESCC.

The utility of Schlafen 11 (SLFN11) expression as a predictive biomarker for platinum‐based chemotherapy has been established for cancers from different histologies. However, the therapeutic relevance of SLFN11 in bladder cancer (BC) is unknown. Here, we examined the clinicopathologic significance of SLFN11 expression across 120 BC cases by immunohistochemistry. We divided the cases into two cohorts, one including 50 patients who received adjuvant or neoadjuvant platinum‐based chemotherapy, and the other including 70 BC patients treated by surgical resection without chemotherapy. In the cohort of 50 BC cases treated with platinum‐based chemotherapy, the SLFN11‐positive group (n = 25) showed significantly better overall survival than the SLFN11‐negative group (n = 25, P = .012). Schlafen 11 expression correlated significantly with the expression of luminal subtype marker GATA3. Multivariate analyses identified SLFN11 expression as an independent prognostic predictor (odds ratio, 0.32; 95% confidence interval, 0.11‐0.91; P = .033). Conversely, in the cohort of 70 BC cases not receiving platinum‐based chemotherapy, the SLFN11‐positive group (n = 29) showed significantly worse overall survival than the SLFN11‐negative group (n = 41, P = .034). In vitro analyses using multiple BC cell lines confirmed that SLFN11 KO rendered cells resistant to cisplatin. The epigenetic modifying drugs 5‐azacytidine and entinostat restored SLFN11 expression and resensitized cells to cisplatin and carboplatin in SLFN11‐negative BC cell lines. We conclude that SLFN11 is a predictive biomarker for BC patients who undergo platinum‐based chemotherapy and that the combination of epigenetic modifiers could rescue refractory BC patients to platinum derivatives by reactivating SLFN11 expression.

Kinesin family member C1 (KIFC1), a minus end-directed motor protein, is reported to play an essential role in cancer. This study aimed to analyze KIFC1 expression and examine KIFC1 involvement in cisplatin resistance in bladder cancer (BC). Immunohistochemistry showed that 37 of 78 (47.4%) BC cases were positive for KIFC1. KIFC1-positive cases were associated with high T stage and lymph node metastasis. Kaplan-Meier analysis showed that KIFC1-positive cases were associated with poor prognosis, consistent with the results from public databases. Molecular classification in several public databases indicated that KIFC1 expression was increased in basal type BC. Immunohistochemistry showed that KIFC1-positive cases were associated with basal markers 34βE12, CK5 and CD44. KIFC1 expression was increased in altered TP53 compared to that in wild-type TP53. Immunohistochemistry showed that KIFC1-positive cases were associated with p53-positive cases. P53 knockout by CRISPR-Cas9 induced KIFC1 expression in BC cell lines. Knockdown of KIFC1 by siRNA increased the sensitivity to cisplatin in BC cells. Kaplan-Meier analysis indicated that prognosis was poor among KIFC1-positive BC patients treated with cisplatin-based chemotherapy. Immunohistochemistry showed that KIFC1-positive cases were associated with PD-L1-positive cases. High KIFC1 expression was associated with a favorable prognosis in patients treated with atezolizumab from the IMvigor 210 study. These results suggest that KIFC1 might be a promising biomarker and therapeutic target in BC.