The implications and mechanisms of the extra-nuclear nucleolin in the esophageal squamous cell carcinomas

Abstract

In recent decades, the multi-functional protein nucleolin (NCL) has been reported to express outside the nucleus of many cancer cells. However, the expression and role of the extra-nuclear NCL in esophageal squamous cell carcinoma (ESCC) were not well characterized. Here, NCL was detected by immunohistochemistry and Western blotting in 60 ESCC tissues. Further, the associations of NCL, EGFR, CXCR4 and Ki67 were analyzed by in vitro assays. Our results showed that NCL expression in all 40 cases of ESCC tissues with metastasis was extensively located in the nucleus, cytoplasm and cell membrane (extra-nucleus), while NCL expression in all 20 cases of ESCC without metastasis was merely limited into the nucleus (intra-nucleus).The extra-nuclear NCL expression was positively correlated with the expression of EGFR, CXCR4 and Ki67 and serves as an independent prognostic factor for ESCC patients. In vitro, NCL siRNA (si-NCL) efficaciously affected the expression of EGF or SDF-1-induced p-AKT, p-ERK and Ki67. Also, NCL siRNA inhibited the capacity of migration and invasion of ECA109 cells. In conclusions, our study suggests that NCL is implicated in the initiation and transduction of EGFR and CXCR4 signaling and further up-regulates Ki67 expression to modulate the biological behaviors of ESCC. Clinically, the extra-nuclear NCL expression can be used as an important indicator to determine metastasis and predict the prognosis, which help develop new therapeutic strategies against ESCC.

Phosphorylation of nucleolin is indispensable to its involvement in the proliferation and migration of non-small cell lung cancer cells

“…levels of nucleolin/P-nucleolin expression. These are results are consistent with those of previous studies (24,25).…”

“…Nucleolin is detectable in cancer cells and is involved in the development of cancer. It has also been associated with poor prognosis for a variety of types of cancer (24,25). For example, nucleolin inhibits P53 and enhances Bcl-2 and protein kinase B (Akt) expression to promote the proliferation of human glioma cells (26).…”

Meeting the needs of breast cancer: A nucleolin’s perspective

“…The subcellular location of the protein reflected differences in the patient's prognosis, where high cytoplasmic staining was associated with a significant recurrence rate and shortened survival rate (log-rank p < 0.0001) 253 . Similar results were reported for esophageal squamous cell carcinomas, in which extra-nuclear expression of nucleolin was significantly correlated with metastatic disease and associated with poor overall survival (log-rank p < 0.000) 469 . Nevertheless, the pattern of nucleolin staining associated with malignancy and cancer progression is not the same for other types of tumors.…”

“…Recent studies have also reported nucleolin overexpression in human-derived tumor tissues as an unfavorable predictor, related to a higher risk of recurrence and worse overall survival of patients, in a variety of neoplasias 253,256,257,259,467,468 . Moreover, the predictive power of nucleolin in a pattern-dependent manner was shown for some types of neoplasias 251,253,254,257,469 . In gastric tumors, both nucleolar and cytoplasmic nucleolin staining was observed, while only nucleolar staining was identified in non-malignant tissues.…”

Different localization of fluorescently labeled N- and C-termini of nucleolin variants in human glioblastoma cell culture

“…In addition, in some types of malignant tumors, extranuclear cytoplasmic nucleolin has been shown to correlate with poor prognosis. A similar pattern has been found in lung and esophagus cancers [Qi et al 2015;Xu et al 2016]. Nucleolin has also been shown to play an important role in breast tumors (Moura et al 2012) and to be even associated with tumor angiogenesis [Christian et al 2003].…”