TFAP2A potentiates lung adenocarcinoma metastasis by a novel miR-16 family/TFAP2A/PSG9/TGF-β signaling pathway

Abstract

Transcription factor AP-2α (TFAP2A) was previously regarded as a critical regulator during embryonic development, and its mediation in carcinogenesis has received intensive attention recently. However, its role in lung adenocarcinoma (LUAD) has not been fully elucidated. Here, we tried to investigate TFAP2A expression profiling, clinical significance, biological function and molecular underpinnings in LUAD. We proved LUAD possessed universal TFAP2A high expression, indicating a pervasively poorer prognosis in multiple independent datasets. Then we found TFAP2A was not indispensable for LUAD proliferation, and exogenous overexpression even caused repression. However, we found TFAP2A could potently promote LUAD metastasis possibly by triggering epithelial–mesenchymal transition (EMT) in vitro and in vivo. Furthermore, we demonstrated TFAP2A could transactivate Pregnancy-specific glycoprotein 9 (PSG9) to enhance transforming growth factor β (TGF-β)-triggering EMT in LUAD. Meanwhile, we discovered suppressed post-transcriptional silencing of miR-16 family upon TFAP2A partly contributed to TFAP2A upregulation in LUAD. In clinical specimens, we also validated cancer-regulating effect of miR-16 family/TFAP2A/PSG9 axis, especially for lymph node metastasis of LUAD. In conclusion, we demonstrated that TFAP2A could pivotally facilitate LUAD progression, possibly through a novel pro-metastasis signaling pathway (miR-16 family/TFAP2A/PSG9/ TGF-β).

Distinct cell states define the developmental trajectories of mucinous appendiceal neoplasms towards pseudomyxoma metastases

“…We identified regulatory genes including TFAP2A , TEAD4 and CD59 . These genes have been shown to promote EMT in lung and colon cancer, among other malignancies [56–58]. Overall, the regulon analysis identified a series of regulatory genes that contribute to metastatic PMPs.…”

Determination of WWOX Function in Modulating Cellular Pathways Activated by AP-2α and AP-2γ Transcription Factors in Bladder Cancer

“…The data on the role of WWOX, AP-2α and AP-2γ in the regulation of MAPK [22][23][24], Wnt [25][26][27], Ras [28][29][30] and PI3K-Akt [31][32][33] signaling are available; however, no influence on Rap1 signaling was found in the literature, suggesting that these could be novel observations. Aside from signal transduction, WWOX and two AP-2 factors are implicated in adhesion [34][35][36], migration [24,37,38], axon guidance (indirectly) [39][40][41] and regulation of extracellular matrix [42][43][44] or miRNA [45,46]. Afterwards, these pathways/processes were visualized as KEGG graphs to present differences and similarities between 'alpha' and 'gamma' comparisons.…”

Knockdown of ubiquitin-conjugating enzyme E2T (UBE2T) suppresses lung adenocarcinoma progression via targeting fibulin-5 (FBLN5)

“…The lung adenocarcinoma cell lines (H1975 and H1650) and normal human bronchial epithelial cell line (HBE) used in this study were purchased from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China). All the cells were cultured in DMEM with 10% FBS and maintained in an incubator at 37°C under 5% CO 2 conditions [ 32 ].…”

“…An equal amount of protein was separated by 10% sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and then transferred to polyvinylidene difluoride (PVDF) membranes (Millipore, CA, USA). After blocking with 5% skimmed milk for 2 h, the membranes were incubated with primary antibodies specific for UBE2T (1:1000, ab140611, Abcam), FBLN5 (1:500, ab66339, Abcam), Bcl-2 (1:2000, ab182858, Abcam), Bax (1:1000, ab32503, Abcam), cleaved-caspase-3 (1:500, ab32042, Abcam), pro-caspase-3 (1:1000, ab32499, Abcam), p-ERK (1:2000, Cell Signaling Technology, #4370), ERK (1:1000, Cell Signaling Technology, #4695), p-GSK3β (1:2000, ab75814, Abcam), GSK3β (1:2000, ab32391, Abcam), β-catenin (1:1000, Cell Signaling Technology, #8480), β-actin (1:1000, ab8227, Abcam) at 4°C overnight, followed by HRP-conjugated secondary antibody (1:2000, ab205718, ab6789, Abcam) for 1 h. The positive bands were detected by using an Enhanced Chemiluminescence Kit (Thermo Fisher Scientific) [ 32 ].…”