| BACKGROUND: It has been reported that CD147and CD98heavy chain(CD98hc) form a complex on cell plasma membrane of several cancers.However, whether this complex exists in non-small cell lung cancer (NSCLC)cells and mediates the prognosis of NSCLC patients remains to be elucidated.CD147/EMMPRIN (extracellular matrix metalloproteinase inducer) is a highlyglycosylated transmembrane protein that belongs to the immunoglobulinsuperfamily. A series of previous studies have reported that CD147is highlyover-expressed on the surface of various malignant tumor cells and elevatedCD147expression is significantly associated with the tumor malignancy. CD147mainly functions as a cellular adhesion molecule to induce the secretion ofextracellular matrix metalloproteinases (MMPs) in tumor local environment andthus promote tumor invasion and metastasis. In addition, CD147is a multifunctional protein that has also been implicated in cell metabolism,regulation of apoptosis, angiogenesis, and drug resistance. CD98is acell-surface heterodimer formed by the covalent linkage of CD98heavy chain(CD98hc, also called4F2hc) with one of at least six different light chains.CD98hc as a multifunctional transmembrane glycoprotein is strongly implicatedin amino acid transport through regulating the expression and cellularlocalization of the amino acid transporting activity of the light chain. CD98hcalso interacts with certain integrin β-subunits to mediate signaling events thatcontrol cell migration, survival, proliferation, and adhesion/polarity. Recently, agrowing body of evidence has come to light, indicating that CD98hc isover-expressed on the cell surface of many cancers and increased CD98hcexpression correlates with the development, progression, and metastaticpotential of tumors. Previous studies have reported that both CD147andCD98hc were significantly over-expressed in NSCLC tissues. Furthermore, theoverexpression of both molecules has been respectively demonstrated to beassociated with poor prognosis of the NSCLC patients. More importantly, arecent study has confirmed the presence of a cell surface “supercomplex†inhuman cell lines HT1080(fibrosarcoma), SW480(colorectal adenocarcinoma),and MCF-7(breast adenocarcinoma) using a covalent cross-linking approachfollowed by mass-pectrometry identification. It was concluded that CD147andCD98hc play a central organizing role within this “supercomplex†that is criticalfor cellular energy metabolism, potentially through the coordination of lactateand amino acid transportation. These lines of evidence lead us to investigatewhether the CD147-CD98hc complex exists on the surface of NSCLC cells andinfluences the clinical prognosis of patients in a synergistic way. METHODS AND RESULTS: The expression of both CD147andCD98hc was assessed in a cohort of241Chinese NSCLC patients whounderwent resection using immunohistochemical staining and examined inNSCLC cell lines using Western blot. Then, the relationship between CD147and CD98hc expression was analyzed. We further investigated the prognosticsignificance of CD147and CD98hc expression using multivariate Coxproportional hazards analysis.Both CD147and CD98hc were significantlyup-regulated in NSCLC tissues and their expression levels were significantlycorrelated (P <0.001). Immunoflurenece staining and co-immunoprecipitationdemonstrated that CD147and CD98hc could form a complex in lung cancercells. Compared to NSCLC patients with CD147-/CD98hc-, those withCD147+/CD98hc+exhibited a significantly poor overall survival with a hazardratio [HR] of2.14,(P=0.031) and a significantly increased risk of recurrencewith a HR of2.04(P=0.022). MTT assay demonstrated that the proliferation oflung cancer cell A549was significantly inhibited by CD147and CD98hcsiRNAs in a synergetic manner.CONCLUSIONS: Our findings indicate that CD147-CD98hc complexsignificantly contributes to poor prognosis of NSCLC patients partially throughpromoting cell proliferation. |
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