Uterine papillary serous carcinoma (UPSC) is a rare type of endometrial cancer. Besides, highly aggressive endometrial carcinoma is characterized by early metastatic spread, high recurrence rate, and poor prognosis compared with type I endometrial carcinoma. Previous studies have evaluated several prognostic factors of UPSC such as stage, age, depth of myometrial, tumor size, lymphatic vascular space invasion (LVSI), grade, tumor markers, and cytoreductive surgery, however, their findings are inconsistent[12]. Of note, most findings indicate that myometrial invasion and tumor stage highly influence the prognosis of UPSC patients. Reports by Black and his colleagues indicated that myometrial invasion and tumor stage were the main factors for UPSC prognosis[13]. Elsewhere, a study showed that LVSI is the only independent prognostic factor for overall survival(OS)[14]. This study reported that myometrial invasion and FIGO stages were risk factors for a worse UPSC prognosis, however, there was no significant difference in LVSI, the tumor grade, P53 and Ki-67 expression. Additionally, the multivariate analysis reported myometrial invasion as an independent prognostic for poor survival of UPSC. Considering the contradicting results from previous studies, we supposed that a lack of patient numbers and limited follow-up time may affect the accuracy of statistical results. Therefore, larger patient samples are needed for a similar study to clarify the UPSC prognosis.
Notably, UPSC has similar characteristics with the ovarian serous carcinoma compared to type I endometrial carcinoma. They include the tendency to metastasize on the peritoneal surfaces and lymph node, occurrence of ascites, and upper abdominal invasion[3]. However, UPSC is potentially chemoresistant. In our previous research, we reported that high TXNDC17 expression is associated with poorer prognosis of ovarian cancer patients. Moreover, TXNDC17 promotes paclitaxel resistance by inducing autophagy in ovarian cancer[7]. This study reports that TXDNC17 is overexpressed in UPSC thereby is associated with chemoresistance and is a risk factor for a worse UPSC prognosis.
Besides, TXNDC17 is a ubiquitous cytosolic protein expressed in mammalian tissues. It contains Trx-like active center proteins, functions as a disulfide reductase and peroxidase, and maintains redox homeostasis in cells[8]. Limited information on the function of TXNDC17 exists, however, recent studies have reported that TXNDC17 is involved in the TNF-αsignal transduction pathway (a stimulating pathway for cellular autophagy) regulation [15]. Moreover, autophagy has been reported as one of the modalities of cell death occurring after chemotherapy and is an underlying mechanism for chemoresistance in tumor cells[16]. We examined the association of the expression between TXDNC17 and BECN1, a key regulator of autophagy, to determine whether autophagy is associated with TXNDC17-related poor prognosis and chemoresistance. Of note, a significant positive correlation between TXDNC17 and BECN1 expression in UPSC was observed.
Furthermore, TXNDC17 was reported as a risk factor for poor UPSC prognosis and is remarkably correlated to chemoresistance and higher BECN1 expression. BECN1 expression in UPSC was determined and patients showing BECN1 overexpression were more likely to develop advanced stage and depth myometrial invasion compared to BECN1 negative patients. Also, patients with TXDNC17high /BECN1high exhibited the shortest survival in UPSC, and patients with TXDNC17high /BECN1high were more likely to have an advanced stage, depth myometrial invasion, and chemoresistance. Moreover, multivariate analysis showed that TXNDC17 expression is an independent prognostic factor for overall survival. This confirmed that TXNDC17 is associated with poor prognosis and chemoresistance by inducing autophagy in UPSC.
Autophagy can cause type II programmed cell death. Effective activation of autophagy confers stress tolerance and maintains cell survival, however excessive or sustained autophagy potentially induce cell death [17]. Besides, autophagy can provide cells with the ability to adapt and thrive in new hostile adverse environments by protecting cancer cells from undesired threats in late tumor stages[18]. Also, autophagy is associated with recurrence, metastasis, and chemotherapy resistance in many cancer types[19-21]. Previously, we reported that autophagy maintains the stemness of ovarian cancer stem cells[22] and TXNDC17 promotes paclitaxel resistance by inducing autophagy in ovarian cancer[7]. Other studies also have reported that STAT3-dependent TXNDC17 expression mediates paclitaxel resistance by inducing autophagy in human colorectal cancer cells[10]. Additionally, suberoylanilide hydroxamic acid has been reported to sensitize neuroblastoma to paclitaxel by inhibiting TXNDC17-mediated autophagy[23]. In this study, we observed TXNDC17 and BECN1 co-expression in some UPSC and TXNDC17 overexpression caused higher BECN1 expression, therefore, it is associated with poor patient prognosis. Moreover, TXNDC17 expression was an independent prognostic factor for overall survival and associated with chemoresistance and is thus a potential target in UPSC therapeutics. Combining the novel targeted therapies that stimulate autophagy with conventional anticancer drugs may provide a new treatment for UPSC, therefore should further be investigated.