High stathmin 1 expression is associated with poor prognosis and chemoradiation resistance in esophageal squamous cell carcinoma

Abstract

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...

Low STMN1 is associated with better prognosis in Asian patients with esophageal cancers: a meta-analysis

“…Of these, two studies were discarded as they used the data from the same patient population, and the other two studies did not provide su cient data. Finally, a total of eight studies [ 7,[15][16][17][18][19][20][21] retrospective studies were included, which encompassed a total of 1240 patients with esophageal cancer. The study selection process is presented in Fig.…”

“…Next, we examined the correlation between STMN1 expression and DFS in esophageal cancer patients. A total of three articles [ 7,16,17] were included. Any statistical heterogeneity was not detected between the studies (I 2 =0%), and so the xed effects model was used.…”

“…Five studies [ 7,15,17,19,21] reported the 5-year survival rate in patients with different expression levels of STMN1, and slightly signi cant heterogeneity was detected (I 2 =56%). Therefore, a random effects model was used for the meta-analysis.…”

“…Five studies [ 7,16,[18][19][20] reported a number of patients with high vs. low expression of STMN1 in different clinical stages of esophageal cancer, no statistical heterogeneity was noted between the studies (I 2 =0%). Therefore, a xed effect model was used.…”

“…Therefore, biological indicators related to the development and prognosis of esophageal cancer are a prerequisite. Nevertheless, STMN1 has been shown to play a key role in the prognosis of esophageal cancer, deeming it as a cancer-associated gene [7][8][9][10].…”