RAC1b overexpression in papillary thyroid carcinoma: a role to unravel

Abstract

Context: The BRAF V600E mutation is the most frequent genetic alteration in papillary thyroid carcinoma (PTC). In colorectal cancer, BRAF V600E was described to functionally cooperate with RAC1b, a hyperactive splice variant of the small GTPase RAC1, to sustain cell survival. This interplay has never been investigated in PTCs.Objective: We aimed to analyze the expression of RAC1b in PTC and correlate its expression with BRAF V600E mutational status, histopathological features, and clinical outcome. Patients and methods: Sixty-one patients and 87 samples (61 PTCs and 26 normal thyroid tissues) were included. Patients were divided into two groups based on longitudinal evolution and final outcome. RAC1b expression levels were determined by quantitative RT-PCR and western blotting. Results: RAC1b was expressed in thyroid and overexpressed in 46% of PTCs. Neither RAC1b overexpression nor V600E mutation correlated with histopathological features classically associated with worse prognosis. RAC1b overexpression was significantly associated with both V600E mutation (PZ0.0008) and poor clinical outcome (PZ0.0029). Whereas BRAF V600E alone did not associate with patient outcome (PZ0.2865), the association of RAC1b overexpression with BRAF V600E was overrepresented in the group with poorer clinical outcome (PZ0.0044). Conclusions: Present results document, for the first time, expression of RAC1b in normal thyroid cells as well as overexpression in a subset of PTCs. Furthermore, they suggest a possible interplay between BRAF V600E and RAC1b contributing to poor clinical outcome. Future studies are needed to clarify the oncogenic potential of RAC1b in thyroid carcinogenesis.

Sanguinarine inhibits Rac1b-rendered cell survival enhancement by promoting apoptosis and blocking proliferation

“…However, tumor cells with up-regulated Rac1b may partially survive this situation and thus greatly aggravate the process of the diseases. Our results support previous reports showing that up-regulated Rac1b can contribute to the tumor progression and metastasis [6,[16][17][18] .…”

“…Apart from its constitutive activity, significantly upregulated Rac1b expression has been reported to be deeply involved in tumorigenesis and the metastasis of colorectal, breast, lung, and thyroid cancers [6,[16][17][18] . Transient overexpression of Rac1b in cultured cells was able to promote cell proliferation [19] .…”

Phosphorylation of SRSF1 by SRPK1 regulates alternative splicing of tumor-related Rac1b in colorectal cells

“…One particular example is the tumor-related splicing variant Rac1b, an isoform of the signaling GTPase Rac1 (Matos et al 2003), in which a usually skipped exon 3b is retained. The resulting protein isoform Rac1b is overexpressed in a specific subtype of colorectal tumors and required to sustain tumor cell survival (Jordan et al 1999;) but was also reported in breast, lung, and thyroid tumors (Schnelzer et al 2000;Radisky et al 2005;Liu et al 2012;Stallings-Mann et al 2012;Silva et al 2013;Zhou et al 2013). Interestingly, Rac1b was found to be predominantly in the signaling-competent GTP-bound conformation (Schnelzer et al 2000;Matos et al 2003;Fiegen et al 2004;Radisky et al 2005), so that small changes in its expression level yield significant cellular responses.…”

Targeting the serrated pathway of colorectal cancer with mutation in BRAF

“…In this CRC study, RAC1b overexpression constituted a marker of poor prognosis. Interestingly, RAC1b overexpression also correlated with the BRAF-V600E mutation and poor prognosis in 68% of papillary thyroid carcinoma [113]. In contrast, no correlation was reported for RAC1b and BRAF mutation in melanoma cell lines [102].…”