Abstract
Pulmonary neuroendocrine tumors (PNTs) comprise different neoplasms, ranging from low grade carcinoids to the highly malignant small cell lung cancers. Several studies identified the cytoskeleton protein Filamin A (FLNA) as determinant in cancer progression and metastasis, but the role of FLNA in PNT aggressiveness and progression is still unknown.We evaluated FLNA expression in PNTs with different grade of differentiation, the role of FLNA in cell proliferation, colony formation, angiogenesis, cell adhesion and migration in PNT cell line (H727 cells) and primary cultures and the possible interaction between FLNA and Rap1-GTPase. FLNA is highly expressed in PNTs with high malignant grade. FLNA silencing reduces cyclin D1 levels (-51±5, p<0.001) and cell proliferation in PNT cells (-37±4, p<0.05), colony formation and VEGF expression (-39±9%, p<0.01) in H727 cells.FLNA and Rap1 co-localize in cellular protrusions and FLNA silencing up-regulates Rap1 expression (+73±18%, p<0.01).Rap1 silencing prevents cell adhesion increase (+43%±18%, p<0.01) and cell migration decrease (-56±7%, p<0.01) induced by FLNA silencing, without affecting cell proliferation reduction. In conclusion, FLNA is implicated in PNT progression, in part through Rap1, thus providing a potential diagnostic and therapeutic target.
Highlights
Pulmonary neuroendocrine tumors (PNTs) comprise a spectrum of neoplasms, ranging from low grade typical carcinoids via the intermediate grade atypical carcinoids to the highly malignant small cell lung cancers [1]
In order to establish whether FLNA is involved or not in this phenomenon we evaluated the correlation of FLNA expression patterns in different PNT stages, we assessed the role of this cytoskeleton protein in influencing cell mobility, cell proliferation, colony formation, angiogenesis, focusing on the potential interaction between FLNA and Rap1
In order to study the possible relationship between FLNA and tumor aggressiveness, we evaluated FLNA expression in different PNT stages by immunohistochemistry using PNT samples, ranging from low grade typical carcinoids (TP) (n=40), atypical carcinoids (AT) (n=11) to the highly malignant large cell lung carcinoma (LCLC) (n=10) and small cell lung cancers (SCLC) (n=5)
Summary
Pulmonary neuroendocrine tumors (PNTs) comprise a spectrum of neoplasms, ranging from low grade typical carcinoids via the intermediate grade atypical carcinoids to the highly malignant small cell lung cancers [1]. Increasing evidence demonstrated that FLNA is pivotal for regulation of matrix cytoskeleton signaling by binding to integrins, which are essential for maintaining directed cell migration and adhesion [6], and for coordination of GTPase signaling factors, leading the formation of lamellipodia and filopodia [11]. In this respect, Rap small GTPase is involved in the control of cell migration and adhesion by enhancing integrin-mediated cell–matrix attachment in several cell types [12]
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