LPCAT1 promotes brain metastasis of lung adenocarcinoma by up-regulating PI3K/AKT/MYC pathway

Abstract

Background Brain metastasis (BM) is associated with poor prognosis, recurrence, and death in patients with non-small cell lung cancer (NSCLC). Lysophosphatidylcholine acyltransferase 1 (LPCAT1) has been reported to be involved in the progression, metastasis and recurrence of malignancies. However, the potential role of LPCAT1 in NSCLC remains poorly understood. This study was aimed to identify genes involved in lung adenocarcinoma (LUAD) brain metastasis, and look into the role of LPCAT1 in LUAD progression. Methods We used integrative genomic analysis to identify genes involved in lung adenocarcinomas. LPCAT1 expression was evaluated in tumor tissues from LUAD patients and LUAD cell lines. The role of LPCAT1 was subsequently investigated both in vitro and in vivo. The mechanism underlying the involvement of LPCAT1 in LUAD progression was explored with the activator of PI3K/AKT pathway. RNA sequencing was performed to confirm the involvement of LPCAT1 and associated pathway in LUAD brain metastasis. Results LPCAT1 was up-regulated in LUAD tissues and cell lines. shRNA-mediated depletion of LPCAT1 not only abrogated cell proliferation, migration and invasion in vitro, but also arrested tumor growth and brain metastases in vivo. Notably, LPCAT1 at least partially influenced LUAD progression through PI3K/AKT signal pathway by targeting MYC transcription. Moreover, expression of LPCAT1 was higher in tissues of LUAD patients with BM than those without BM as revealed by IHC staining, RNA-Sequencing and qPCR analysis. Finally, elevated LPCAT1 expression in patients with lung adenocarcinomas was associated with a poor clinical outcome. Conclusions This study showed that LPCAT1 works as a regulator of cell metastasis and may serve as a novel therapeutic target for BM in lung adenocarcinoma. Electronic supplementary material The online version of this article (10.1186/s13046-019-1092-4) contains supplementary material, which is available to authorized users.

SKA3 promotes lung adenocarcinoma metastasis through the EGFR–PI3K–Akt axis

“…We further assessed the role of SKA3 in EMT processes [22][23][24][25] but no associations were observed. Upon further analysis, we found that AKT activation strongly correlated with SKA3 expression, and that the expression of MMP following SKA3 silencing decreased in a manner that could be rescued by exogenous AKT overexpression, suggestive that SKA3 influences MMP-2, -7 and -9 to promote of LUAD occurrence and development [26][27][28][29][30][31][32]. These data further suggested that the selective modulation of SKA3 during EGFR-PI3K-AKT signaling in LUADs leads to EGF modulation, with no effects on HGF-signaling.…”

Brain Metastases in Lung Cancers with Emerging Targetable Fusion Drivers

“…This implicates the PI3K/Akt/mTOR pathway as a mechanism by which fusion-driven NSCLC develop BM. LPCAT1 gene expression may play a key role in promoting BM via the PI3K pathway [36]. Furthermore, prior studies of BM in breast cancer and melanoma have also illustrated the importance of PI3K pathway upregulation [37][38][39].…”

MTHFD2 Regulates the AKT/MYC Signaling Pathway in Bladder Cancer and Promotes Proliferation, Viability and Migration in Vitro

“…As another signaling pathway of regulate metabolism, the oncogenic Myc pathway is reported to activate and reinforce metabolic pathways in transformed cells [28]. On the other hand, MYC is a well-established downstream effector molecule of the AKT through which AKT governs multifaceted procedure of various malignancies [29,30]. To further detail the MTHFD2-medidated BC malignancy, luciferase and rescue assays validated that the regulatory association between AKT and MTHFD2 through activation of MYC.…”

“…Thereofore,MTHFD2 partly regulates metabolic alternation by activating the AKT/MYC signaling pathway, which can maintain sufficient cell-autonomous nutrient uptake and enable tumor cells to overcome normal physiologic constraints for cell doubling. However, aberrance of Akt and Myc pathways are examined in various types of cancer [29,30,31], which may support the universality of metabolic remodeling in tumor cells. Therefore, MTHFD2 may have a more complex regulatory network in tumor cell proliferation and tumorigenesis.…”