Upregulated TRIO expression correlates with a malignant phenotype in human hepatocellular carcinoma

Abstract

Triple functional domain protein (TRIO) is an evolutionarily conserved Dbl family guanine nucleotide exchange factors (GEFs) involved in cell proliferation and progression of some types of cancer. However, the expression and prognostic role of TRIO in hepatocellular carcinoma (HCC) have not yet been determined. Therefore, we attempted to determine the impact of TRIO on the clinical outcome of HCC patients to further identify its role in HCC. TRIO expression was examined using quantitative real-time PCR (qRT-PCR) and Western blotting in nonmalignant liver cells, HCC cells, and 93 paired of HCC tissues and adjacent noncancerous tissues. Statistical analyses were used to assess associations between TRIO expression and clinicopathological and prognostic factors. Small interfering RNA (siRNA)-mediated TRIO inhibition was performed in Hep3B and Huh7 cells to elucidate its roles in HCC. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was employed to measure cell proliferation, and apoptosis assay was analyzed by flow cytometry, respectively. Adhesion and transwell invasion assay were performed to determine the invasion ability of HCC cells in vitro. TRIO was significantly upregulated in the HCC cell lines and tissues compared with the nonmalignant liver cells and adjacent noncancerous liver tissues. In addition, high TRIO expression level associated with lymph node metastasis (P = 0.0183), clinical tumor node metastasis (TNM) stage (P = 0.0.0106), and decrease in overall survival (OS) (P = 0.017). Knockdown of TRIO on Hep3B and Huh7 cell lines suppressed cell proliferation and migration and induced apoptosis. Furthermore, silencing TRIO expression led to decrease of ras-related C3 botulinum toxin substrate 1 (Rac1), p-P38, B cell lymphoma 2 (BCL-2), and matrix metallopeptidase 9 (MMP-9). Our results demonstrated that TRIO protein expression is elevated and associated with a worse over survival rates in patients with HCC. Aberrant expression of TRIO might play an important role in HCC through promoting cell proliferation and invasion, and TRIO may be a novel therapeutic target for the treatment of HCC.

Knockdown of Trio by CRISPR/Cas9 suppresses migration and invasion of cervical cancer cells

“…Rho-GTPase proteins participate in cell motility and actin cytoskeleton reorganization (18). RhoA is a member of the Rho-GTPase proteins and acts as a switch between the active GTP-bound form and inactive GDP-bound form.…”

“…Since Trio controls a wide range of cellular processes, dysregulation of its activity is related to the emergence of diseases. Trio was demonstrated to be highly upregulated in urinary bladder tumors (11), soft tissue sarcomas (12), breast cancer (13), and various other types of cancer (11)(12)(13)(14)(15)(16)(17)(18)(19). Higher Trio levels were closely related to invasive tumor phenotype, high tumor grade, and rapid tumor cell proliferation in breast tumors (13).…”

“…Lymph node metastasis acts as an important unfavorable prognostic factor and a primary cause of cancer-related deaths (28). Previous studies have reported that Trio was involved in some types of cancer development (11)(12)(13)(14)(15)(16)(17)(18)(19). High expression of Trio was associated with rapid tumor cell proliferation and invasive tumor growth (18).…”

Validation of Novel Prognostic Biomarkers for Early-Stage Clear-Cell, Endometrioid and Mucinous Ovarian Carcinomas Using Immunohistochemistry

“…It should however be noted that only 4/25 cancer samples were characterized as CCC. TRIO plays a role in cell proliferation and progression of cancer, wherein higher protein expression has been shown to be associated with worse outcome (OS) (44). To the best of our knowledge, we are the first to report an association between CCC-related biomarkers (ARPC2, CCT5, GNB1, KCTD10, NUP155, RPL13A, RPL37, SETD3, SMYD2, TRIO) and prognosis.…”

RHOB expression controls the activity of serine/threonine protein phosphatase PP2A to modulate mesenchymal phenotype and invasion in non-small cell lung cancers

“…TRIO was also recently implicated in the invasion process in colorectal and hepatocellular carcinoma. 29,30 But while it was recently reported that AKT phosphorylates TIAM1 and thereby increases its stability, 31 nothing is currently known about the regulation of TRIO by AKT. Very recently, Marcos-Ramiro and colleagues also reported a relationship between RHOB and RAC1 in the endothelium, where RHOB was shown to negatively regulate RAC1 activity and trafficking at endosomes after injury, resulting in the inhibition of barrier recovery after acute contraction.…”