<p>FRMPD1 activates the Hippo pathway via interaction with WWC3 to suppress the proliferation and invasiveness of lung cancer cells</p>

Abstract

Purpose: The expression of FERM-domain-containing protein-1 (FRMPD1)/FERM and PDZ domain-containing protein-2 (FRMD2) in malignant tumors, including lung cancer, and its underlying molecular mechanism have not been reported yet. Materials and methods: Immunohistochemistry was performed to analyze the expression of FRMPD1 in lung cancer tissues, and statistical analysis was applied to analyze the relationship between FRMPD1 expression and clinicopathological factors. The biological effects of FRMPD1 on lung cancer cell proliferation and invasion were determined by functional experiments both in vivo and in vitro. Immunoblotting, RT-qPCR, dual-luciferase assay, and immunofluorescence were performed to demonstrate whether FRMPD1 stimulates Hippo signaling. Co-immunoprecipitation assays were used to clarify the underlying role of FRMPD1 in Hippo pathway activation via interaction with WW and C2 domain containing protein-3 (WWC3). Results: We found that FRMPD1 expression in lung cancer specimens was lower than that in normal bronchial epithelium and normal submucosal glands. FRMPD1 expression had a negative correlation with age, Tumor-Node-Metastasis (TNM) stage, lymph node metastasis, as well as poor prognosis. Moreover, ectopic expression of FRMPD1 significantly inhibited the proliferation and invasion of lung cancer cells, and inhibition of FRMPD1 expression led to opposite effects. Mechanistically, we found that FRMPD1 interacted with the C-terminal PDZ binding motif of WWC3 via its PSD95/DLG/ZO1 (PDZ) domain and promoted the phosphorylation of large tumor suppressor-1 (LATS1), thus inhibiting the nuclear translocation of yes-associated protein (YAP). Conclusion: FRMPD1 could activate the Hippo pathway and ultimately inhibit the malignant behavior of lung cancer cells through its interaction with WWC3. This work will provide an important experimental basis for the discovery of novel biomarkers of lung cancer and the development of targeted drugs.

Hypoxic bone marrow mesenchymal cell‐extracellular vesicles containing miR‐328‐3p promote lung cancer progression via the NF2‐mediated Hippo axis

“…The Hippo pathway is well‐known to be implicated in the biological functions of a variety of cancers 37 . In concord with our present findings, the activated Hippo pathway was previously shown to be capable of inhibiting the proliferation and invasion of lung cancer cells 38 . Also, the NF2 gene is reported to exert its effects through the Hippo pathway to regulate cell proliferation and apoptosis 39 .…”

“…invasion of lung cancer cells 38. Also, the NF2 gene is reported to exert its effects through the Hippo pathway to regulate cell proliferation and apoptosis 39.…”

<p>PWP1 Promotes the Malignant Phenotypes of Lung Cancer Cells by Interacting with DVL2 and Merlin</p>

“…Increased nuclear translocation of YAP drove CTGF and Cyclin E transcription. 22,23 By combining PWP1 overexpression with DVL2 or Merlin down-regulation, we offset the effects of PWP1 in promoting Wnt signaling activation and inhibiting the Hippo signaling pathway ( Figure 6). These combined effects promoted increased lung cancer cell proliferation and invasion.…”

WWC Proteins: Important Regulators of Hippo Signaling in Cancer

“…WWC3 was identified to interact with the FERM-domain-containing protein-1 (FRMPD1), which is downregulated in NSCLC [ 51 ]. In non-malignant cells, the WWC3–FRMPD1 interaction enhances phosphorylation of LATS1 and Hippo signaling, hindering the transcription of YAP target genes and reducing malignancy.…”

“…In non-malignant cells, the WWC3–FRMPD1 interaction enhances phosphorylation of LATS1 and Hippo signaling, hindering the transcription of YAP target genes and reducing malignancy. However, in NSCLC, WWC3 and FRMPD1 levels are reduced and Hippo signaling is low, which correlates with advanced tumor–node–metastasis stage, lymph node metastasis and poor prognosis [ 51 ].…”