PNMA5 Promotes Bone Metastasis of Non-small-Cell Lung Cancer as a Target of BMP2 Signaling

Abstract

Bone metastases frequently occur in NSCLC patients at the late stage, indicating poor survival. However, mechanisms about the initiation of NSCLC bone metastases remain largely unclear. In our previous reports, BMP2 signaling activation has been found to enhance NSCLC bone metastases through enhancing carcinoma cells migration, invasion, osteoclasts differentiation and osteoblasts immature differentiation. Nevertheless, downstream target genes of BMP2 contributing to those processes still remain unknown. In this project, we find that the expression of Pnma5 is higher in metastatic bone tumors of Lewis lung carcinoma than in metastatic lung tumors and parental Lewis lung cells. Pnma5 overexpression not only can promote cell migration and invasion of NSCLC cells but also tumor-induced osteoclasts differentiation. Interestingly, knockdown of Pnma5 in Lewis lung cells blocks BMP2 signaling from inducing Lewis lung cells migration and invasion. Although BMP2 signaling can promote Lewis lung cells-induced osteoclasts differentiation from macrophages, this effect can also be blocked when Pnma5 is knocked down in Lewis lung cells. Moreover, Pnma5 can promote NSCLC bone metastases in vivo as the downstream target of BMP2. Those results above indicate that BMP2 signaling enhances NSCLC bone metastases via its direct downstream target gene Pnma5. This research reveals the detailed molecular mechanism about how BMP2 signaling contributes to NSCLC bone metastases via PNMA5 and provides a new potential therapeutic target for the treatment of NSCLC bone metastases.

MiroRNA-31-3p Promotes the Invasion and Metastasis of Non-Small-Cell Lung Cancer Cells by Targeting Forkhead Box 1 (FOXO1)

“…Distant metastases often occur to the patient at the advanced stage, leading to a poor prognosis. NSCLC often tends to have bone metastasis [ 6 ], and cell migration and invasion are the key factors for bone metastasis of cancer cells [ 7 ]. Usually, when the patient is diagnosed with NSCLC, the pathological process has already entered the middle or late stage, therefore missing the best treating period [ 8 ], and eventually leading to death.…”

Clinical Efficacy of Osimertinib in Patients with Advanced Non-Small Cell Lung Cancer and Its Effect on Serum CEA and VEGF Expression

“…The Japanese Cancer Institute recommends chemotherapy treatment for patients with advanced NSCLC without surgical indication, of which PC regimen (pemetrexed + cisplatin) is well-recognized [ 3 ] and can efficiently promote apoptosis of tumor cells. However, numerous clinical studies have shown that the PC regimen (pemetrexed + cisplatin) is associated with considerable adverse events and suppression of immune function [ 4 ], which is detrimental to the functional recovery of patients [ 5 ]. It has been confirmed that epidermal growth factor receptor gene mutations are present in 35%–45% of NSCLC patients in China, and the 1st and 2nd generation EGFR complex kinase inhibitors are available for targeted treatment of NSCLC, which substantially prolongs the survival of patients [ 6 ].…”

Muscle and Bone Defects in Metastatic Disease

“…There has been an increased interest in generating new threedimensional (3D) in vitro models including patient-derived xenograft models, organoid, and scaffold models that can mimic native bone microenvironment [176][177][178][179][180][181][182][183][184][185]. In addition, numerous new compounds have been evaluated for their effect and therapeutic potential on metastatic bone disease [186,187,[196][197][198][188][189][190][191][192][193][194][195]. Currently approved therapeutic agents for bone metastases include chemotherapy, radiotherapy, bisphosphonates, and anti-RANKL therapy [199].…”