MMP7-mediated cleavage of nucleolin at Asp255 induces MMP9 expression to promote tumor malignancy

Abstract

Nucleolin (NCL) participates in DNA transcription, ribosomal biogenesis and the regulation of RNA stability. However, the contribution of NCL to tumor development is still not clear. Herein, we found that NCL expression correlated with poor prognosis in lung cancer patients. Overexpressed NCL was predominantly cleaved to C-terminal truncated NCL (TNCL). In lung cancer formation, activation of the epidermal growth factor receptor pathway induced NCL expression, and also the expression of matrix metalloproteinase (MMP) 7, which then cleaved NCL at Asp255 to generate TNCL of 55 kDa. TNCL increased the expression of several oncogenes, including MMP9, anaplastic lymphoma kinase (ALK), HIF1a and CBLB, and decreased the expression of tumor suppressors including BRD4, PCM1, TFG and KLF6 by modulating mRNA stability through binding to the 3'-untranslated regions of their transcripts, thus ultimately enhancing metastasis activity. In conclusion, this study identified a novel role of the cleavage form of NCL generated by MMP7 in stabilizing MMP9 mRNA. We also provide a new insight that MMP7 not only cleaves the extracellular matrix to promote tumor invasion but also cleaves NCL, which augment oncogenesis. Blocking NCL cleavage may provide a useful new strategy for lung cancer therapy.

Association between expression of MMP‐7 and MMP‐9 and pelvic lymph node and para‐aortic lymph node metastasis in early cervical cancer

“…MMP‐7 and MMP‐9 can be activated by downstream transcription factors such as β‐catenin, c‐JUN, PEA3, EGF and LEF‐1 . The most recent study indicated that MMP7 can not only cleave the extracellular matrix (ECM) to promote tumor invasion but also cleaves nucleolin to stabilize MMP9 expression in order to augment oncogenesis . Furthermore, the combined expression of MMP7 and MMP9 has been suggested to be a good marker for the degree of malignancy and for the presence of lymphatic metastasis in esophageal cancer .…”

“…21,22 The most recent study indicated that MMP7 can not only cleave the extracellular matrix (ECM) to promote tumor invasion but also cleaves nucleolin to stabilize MMP9 expression in order to augment oncogenesis. 23 Furthermore, the combined expression of MMP7 and MMP9 has been suggested to be a good marker for the degree of malignancy and for the presence of lymphatic metastasis in esophageal cancer. 24 However, to the best of our knowledge, correlation of MMP7 and MMP9 expressions and their correlation with lymphatic metastasis have not been well established in cervical cancer up to now.…”

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

“…Such diverse and crucial functions of nucleolin indicate the importance of this protein for the functioning of the cell. At the same time, the level of nucleolin has been found to increase in actively proliferating cells (Hsu et al 2015), which is important both for the normal cells of the organism and for pathologically multiplying cells of malignant tumors. In recent years, a large number of articles have been devoted to the study of nucleolin in tumor cells.…”

“…In recent years, a large number of articles have been devoted to the study of nucleolin in tumor cells. It has been shown that during the development of various types of malignant tumors nucleolin interacts with EGFR, Ras and Sp1, and this interaction leads to active tumor growth [Hsu et al 2015;Hung et al 2014]. In addition, in some types of malignant tumors, extranuclear cytoplasmic nucleolin has been shown to correlate with poor prognosis.…”

“…Galzio et al argued that an increase in membrane-localized nucleolin could serve as a poor prognosis indicator and correlate with the level of glioma malignancy [Galzio et al, 2012]. In addition, in the study of cell lines derived from aggressive types of cancer, a large number of shortened splice variants of nucleolin have been identified, which made it possible to suggest a correlation between cell malignancy and increase in diversity of short forms of nucleolin [Hsu et al 2015]. For example, two nucleolin variants of 72 and 55 kDa have been found in lung cancer cell lines, whereas the full-length protein is 110 kDa [Kito et al 2005;Hsu et al 2015].…”