Predominant Rab-GTPase amplicons contributing to oral squamous cell carcinoma progression to metastasis

Abstract

Metastatic oral squamous cell carcinoma (OSCC) is frequently associated with recurrent gene abnormalities at specific chromosomal loci. Here, we utilized array comparative genomic hybridization and genome-wide screening of metastatic and non-metastatic tongue tumors to investigate genes potentially contributing to OSCC progression to metastasis. We identified predominant amplifications of chromosomal regions that encompass the RAB5, RAB7 and RAB11 genes (3p24-p22, 3q21.3 and 8p11–12, respectively) in metastatic OSCC. The expression of these Rab GTPases was confirmed by immunohistochemistry in OSCC tissues from a cohort of patients with a follow-up of 10 years. A significant overexpression of Rab5, Rab7 and Rab11 was observed in advanced OSCC cases and co-overexpression of these Rabs was predictive of poor survival (log-rank test, P = 0.006). We generated a Rab interaction network and identified central Rab interactions of relevance to metastasis signaling, including focal adhesion proteins. In preclinical models, mRNA and protein expression levels of these Rab members were elevated in a panel of invasive OSCC cell lines, and their down-regulation prevented cell invasion at least in part via inhibition of focal adhesion disassembly. In summary, our results provide insights into the cooperative role of Rab gene amplifications in OSCC progression and support their potential utility as prognostic markers and therapeutic approach for advanced OSCC.

Rab11 collaborates E‐cadherin to promote collective cell migration and indicates a poor prognosis in colorectal carcinoma

“…Rab11 has been shown to function in the movement of recycled endosomes to the membrane and regulates epithelial cell polarity [32,33]. It has also been reported to participate in cellular functions and cancerous metastasis [29,[34][35][36][37][38][39]. Our previous work further demonstrated that Rab11 can regulate E-cadherin expression during cell transformation in colon cancer [19].…”

“…A recent study by da Silva et al . demonstrated that the positive expression of Rab11 is correlated with poor survival in oral squamous cell carcinoma. Our data showed that in stage I or II of the disease, a lack of Rab11 expression led to a better survival than positive Rab11 expression.…”

“…The purpose of the current study was to determine the roles of E-cadherin and Rab11 in CRC survival. A recent study by da Silva et al [39] demonstrated that the positive expression of Rab11 is correlated with poor survival in oral squamous cell carcinoma. Our data showed that in stage I or II of the disease, a lack of Rab11 expression led to a better survival than positive Figure 4 Rab11 depletion-suppressed anchorageindependent cell growth.…”

Nuclear accumulation of β‐catenin is associated with endosomal sequestration of the destruction complex and increased activation of Rab5 in oral dysplasia

“…Although endosomal sequestration of the destruction complex has been extensively studied in non‐tumor cells, the identity of molecular players controlling this phenomenon is not completely clear. The latter becomes intriguing, in the light that a subset of endosomal regulators—the Rabs—have gained attention for their role in different pathologies, including cancer . Hence, the identification of Rab5 as a critical factor required for the recruitment of APC, GSK3β, and Axin within early endosomes, and consequently nuclear accumulation of β‐catenin and transcription of target genes, is striking, since Rab5 is upregulated in cancer clinical samples, including lung adenocarcinoma, pancreatic cancer, ovarian cancer, hepatocellular carcinoma, and OSCC .…”

“…Although the mechanisms leading to the endosomal sequestration of the destruction complex have been studied, the identity of endosomal proteins controlling this phenomenon is not completely understood, and most importantly, whether this mechanism is deregulated in premalignant and tumor cells, has not been explored. This is intriguing, because several components and regulators of the endocytic machinery have been shown to undergo either gain or loss of function in different cancers, including OSCC . Specifically, within the family of Rab GTPases, which control endocytic trafficking, Rab5 has been reported to be upregulated in different cancers, including lung adenocarcinoma, pancreatic cancer, ovarian cancer, hepatocellular carcinoma, and OSCC …”