SH3BGRL2 inhibits growth and metastasis in clear cell renal cell carcinoma via activating hippo/TEAD1-Twist1 pathway

Abstract

Background: Clear cell renal cell carcinoma (ccRCC) is one of the most prevalent malignancies in the world, and tumor metastasis is still the main reason for disease progression. Accumulating evidence shows that SH3BGRL2 may play a key role in tumor progression and metastasis. However, the role of SH3BGRL2 in ccRCC has not been systematically investigated and remains elusive. Methods: The clinical significance of SH3BGRL2 was evaluated by bioinformatic analysis and tissue microarray (TMA) samples. SH3BGRL2 expression was determined by RT-PCR, western blot and immunohistochemistry staining. Tumor suppressive effect of SH3BGRL2 was determined by both in vitro and in vivo studies. Western blot, chromatin immunoprecipitation assay and luciferase report assay were applied for mechanism dissection. Findings: SH3BGRL2 was crucial for epithelial-mesenchymal transition (EMT) progression and metastasis in ccRCC. Clinically, SH3BGRL2 was identified as an independent prognostic factor for ccRCC patients. Gain-and loss-of-function results suggested that SH3BGRL2 played a critical role in cell proliferation, migration and invasion. Mechanistically, we found that SH3BGRL2 acted as a tumor suppressor through Hippo/TEAD1 signaling, then TEAD1 altered Twist1 expression at the transcriptional level via directly binding to its promoter region. Interpretation: Our findings established that SH3BGRL2 performed as a tumor suppressor and modulator via Hippo/TEAD1-Twist1 signaling in ccRCC, and the alteration of SH3BGRL2 could serve as a functional response biomarker of tumor progression and metastasis in ccRCC.

Alpha-lipoic acid protects against pressure overload-induced heart failure via ALDH2-dependent Nrf1-FUNDC1 signaling

“…The 2 kb promoter region of FUNDC1 was constructed into the pGL3-basic vector (Promega, Madison, WI). NRCMs were seeded in 24-well plates and were transfected with plasmids using Lipofectamine 3000 (Invitrogen) according to the manufacturer's instruction 26 . After 48 h, cells were lysed and measured according to the manufacturer's instruction using the Dual-Luciferase Reporter Assay System (Promega).…”

LncRNA MNX1-AS1 promotes progression of intrahepatic cholangiocarcinoma through the MNX1/Hippo axis

“…Once the Hippo pathway is inactivated, Yesassociated protein (YAP) and Tafazzin (TAZ) translocated into the nucleus to promote cell proliferation 60 . Numerous studies have also reported that the Hippo pathway participated in the progression of various malignancies 59,[61][62][63][64] .…”

“…Once the Hippo pathway is inactivated, Yes-associated protein (YAP) and Tafazzin (TAZ) translocated into the nucleus to promote cell proliferation 60 . Numerous studies have also reported that the Hippo pathway participated in the progression of various malignancies 59 , 61 – 64 . G9a-derived dimethylated H3K9 (H3K9me2) repressed the expression of large tumor suppressor 2 (LATS2) and promoted the expression of YAP subsequently.…”

CORO6 Promotes Cell Growth and Invasion of Clear Cell Renal Cell Carcinoma via Activation of WNT Signaling

“…Renal cell carcinoma (RCC) is the most common type of kidney cancer, and its incidence continues to rise (Siegel et al, 2019). Clear cell renal cell carcinoma (ccRCC) is the most common type of RCC and accounts for ∼80% of all cases (Choueiri et al, 2007;Yin et al, 2020). Understanding of the biological pathogenesis of ccRCC has led us to identify that von Hippel-Lindau tumor suppressor (VHL)/hypoxia-inducible factor 2 alpha (HIF2α signaling plays a central role in its development.…”