Background Metastatic and refractory gastric cancer (GC) are associated with a poor prognosis; therefore, the identification of prognostic factors and chemosensitivity markers is extremely important. Protein arginine methyltransferase 1 (PRMT1) may play a role in chemosensitivity/apoptosis induction via activation of the tumor suppressor forkhead box O1 (FOXO1). The purpose of this study was to clarify the expression of and relationship between PRMT1 and FOXO1 to evaluate the applicability of PRMT1 as a prognostic marker and a therapeutic tool in GC. Methods We investigated the clinical and functional significance of PRMT1 and FOXO1 in 195 clinical GC samples using immunohistochemistry. We performed suppression analysis of PRMT1 using small interfering RNA to determine the biological roles of PRMT1 in chemosensitivity. Results PRMT1 and FOXO1 in GC samples were predominantly expressed in the nucleus. Patients with lower PRMT1 expression (n = 131) had suppressed nuclear accumulation of FOXO1, higher recurrence after adjuvant chemotherapy, and poorer prognosis than those with higher PRMT1 expression (n = 64). PRMT1 downregulation in GC cells by RNA interference inhibited cisplatin and 5-fluorouracil sensitivity. The expression of phosphorylated FOXO1 and phosphorylated BCL-2 antagonist of cell death was upregulated in PRMT1 small interfering RNA groups. Conclusion Our data suggest that the evaluation of PRMT1 expression in GC is a useful predictor of poor prognosis and recurrence after adjuvant chemotherapy. Moreover, these data suggest that PRMT1 is a promising therapeutic tool for overcoming refractory GC.

High TGFBI expression in ESCC tissues could be a powerful biomarker of poor prognosis and hematogenous recurrence. TGFBI in stromal cells might be a promising molecular target for ESCC treatment.

Abstract. Stathmin 1 (STMN1) is a major cytosolic phosphoprotein regulating microtubule dynamics, thereby playing an important role in cancer progression and resistance to microtubule-binding anticancer agents. We assessed the prognostic significance of STMN1 expression and STMN1-associated resistance to docetaxel and radiation in esophageal squamous cell carcinoma (ESCC) patients. STMN1 expression was evaluated by immunohistochemistry in 172 surgical specimens. The association of STMN1 expression with chemoradiation resistance using docetaxel was examined by comparing expression in 15 biopsy specimens obtained before neoadjuvant therapy to histological grades of post-therapy surgically resected tumors. We also evaluated the effects of STMN1 on sensitivity to docetaxel and radiation in ESCC cell lines. High STMN1 immunoexpression was significantly associated with tumor depth, lymph node metastasis, lymphatic invasion and venous invasion. Survival rates were significantly lower in ESCC patients with high STMN1 expression than in those with low STMN1 expression. Multivariable analysis showed that high STMN1 expression was an independent factor for poor survival. High STMN1 expression was also associated with poor response to neoadjuvant chemoradiotherapy using docetaxel. Knockdown of STMN1 expression enhanced ESCC cell line sensitivity to docetaxel and radiation. STMN1 appears critical for ESCC invasiveness and predicts an unfavorable prognosis in ESCC. IntroductionEsophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with a significant mortality rate (1,2). Despite improvements in the surgical management of ESCC and development of useful chemotherapies and chemoradiotherapies (CRTs), the prognosis of patients with advanced disease remains poor (3-5). Furthermore, the identification of novel therapeutic targets is essential for individual curative adjuvant or neoadjuvant therapies.Stathmin 1 (STMN1) is a major cytosolic phosphoprotein that regulates microtubule dynamics by preventing tubulin polymerization and promoting microtubule destabilization (6). STMN1 is highly expressed in multiple human malignancies and is therefore also known as oncoprotein 18. STMN1 expression correlates with tumor progression and poor prognosis in various cancers (7-17) including ESCC (18). These studies indicated that STMN1 is a fundamental cancer-associated gene and a potential target for the diagnosis and treatment of cancers, including ESCC. However, the exact significance of STMN1 in tumor progression and therapeutic resistance has not yet been elucidated in ESCC patients treated with CRT.The expression of STMN1 is known to be functionally linked to chemosensitivity to microtubule-stabilizing agents such as taxanes, which are widely used anticancer agents. Inhibiting STMN1 expression enhances chemosensitivity to paclitaxel in osteosarcoma cells (19) and ESCCs (20) in vitro, while the overexpression of STMN1 decreases breast cancer cell sensitivity to paclitaxel and vinblastine (7). In Japan, docetaxel is con...

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Our data suggest that high expression of PROX1 in ESCC could be used as an indicator of poor prognosis, and that PROX1 is a promising candidate molecular target for ESCC treatment.

Background/Aim: Several immunoinflammatory and nutritional measures have been reported to be good prognostic indicators for esophageal cancer (EC). However, the association between those markers and the postoperative survival of EC patients remains unclear due to varying study designs and treatment strategies. The aim of this study was to compare the significance of preoperative immunoinflammatory and nutritional measures in patients with EC. Patients and Methods: One hundred and five patients with EC who underwent McKeown esophagectomy with gastric tube reconstruction without neoadjuvant therapy between 2006 and 2014 were included in this study. The prognostic values of preoperative modified Glasgow prognostic score (mGPS), controlling nutritional status (CONUT) score, prognostic nutritional index (PNI), C-reactive protein (CRP)-to-albumin ratio (CAR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were investigated using univariate and multivariate survival analyses. Results: Multivariate analysis revealed that CAR and pathological stage are independent prognostic factors for overall survival (OS). CAR was significantly associated with more advanced pathological stage as both a subject and a continuous variable. Conclusion: Preoperative CAR was an independent prognostic factor for the OS of EC patients who underwent McKeown esophagectomy. The tumor-stage related increase in CAR demonstrated that a high CAR is associated with tumor progression in EC patients.

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BackgroundLymph node metastasis (LNM) is a standard mechanism of cancer progression in esophageal squamous cell carcinoma (ESCC). We aimed to clarify the anatomical mechanism of skip nodal metastasis to mediastinal zones by analyzing the relationship between LNM to sentinel zones and lymphatic vessel counts in the muscle layer adjacent to the outer esophagus.MethodsWe examined the surgical records of 287 patients with ESCC who underwent potentially curative surgery (three-field lymphadenectomy) and whole esophagi, including pharynges and stomachs from 10 cadavers, to determine the number of lymphatic vessels in the intra-outer longitudinal muscle layer adjacent to the outer esophagus of the cervical (Ce), upper thoracic, middle thoracic (Mt), lower thoracic (Lt), and abdominal esophagi (Ae).ResultsThe frequency of LNM to the middle mediastinal and supraclavicular zones, including the Mt and Ce, respectively, was lower than to the upper and lower mediastinal and abdominal zone in patients with superficial and advanced thoracic ESCC. In cadavers, the lymphatic vessel counts of the intra-outer longitudinal muscle layer in the Mt and Ce were significantly lower than those of the Lt and Ae, suggesting that lymphatic flow toward the outside of the Mt and Ce was not more abundant than to other sites.ConclusionOur anatomical data suggested that the absence of intra-muscle lymphatic vessels in the middle mediastinal and supraclavicular zones causes skip LNM in patients with thoracic ESCC. Thus, standard esophagectomy with lymph node dissection, including distant zones, may be appropriate for treating patients with superficial thoracic ESCC.Electronic supplementary materialThe online version of this article (10.1245/s10434-018-6390-0) contains supplementary material, which is available to authorized users.