Rab25 Regulates Invasion and Metastasis in Head and Neck Cancer

Abstract

Purpose Head and neck squamous cell carcinoma (HNSCC) is one of the ten most common cancers with a 50% five-year survival rate, which has remained unchanged for the past three decades. One of the major reasons for the aggressiveness of this cancer is that HNSCCs readily metastasize to cervical lymph nodes that are abundant in the head and neck region. Hence, discovering new molecules controlling the metastatic process as well as understanding their regulation at the molecular level are essential for effective therapeutic strategies. Experimental Design Rab25 expression level was analyzed in HNSCC tissue microarray. We used a combination of intravital microscopy in live animals and immunofluorescence in an in vitro invasion assay, to study role of Rab25 in tumor cells migration and invasion. Results In this study, we identified the small GTPase Rab25 as a key regulator of HNSCC metastasis. We observed that Rab25 is downregulated in HNSCC patients. Next, we determined that re-expression of Rab25 in a metastatic cell line is sufficient to block invasion in a 3D collagen matrix and metastasis to cervical lymph nodes in a mouse model for oral cancer. Specifically, Rab25 affects the organization of F-actin at the cell surface, rather than cell proliferation, apoptosis or tumor angiogenesis. Conclusion These findings suggest that Rab25 plays an important role in tumor migration and metastasis, and that understanding its function may lead to the development of new strategies to prevent metastasis in oral cancer patients.

Downregulation of Rab25 activates Akt1 in head and neck squamous cell carcinoma

“…Therefore, in order to examine the effect of Rab25 in HNSCC the present study was conducted using tissue samples from patients with this disease. In accordance with the results reported by Amornphimolthan et al (32), the present study demonstrated that Rab25 was significantly downregulated in 69.1% and 56.1% of the HNSCC tumor tissue samples at the mRNA and protein levels, respectively. However, in contrast to the results of the study by Amornphimolthan et al (32), Rab25 downregulation was not associated with tumor invasion in the current study (P=0.529).…”

“…It has been shown that the Ras superfamily proteins regulate various steps of vesicular trafficking in eukaryotic cells (34). Rab25, a member of the Ras superfamily, has been demonstrated to be involved in cell proliferation and in protection of cells from apoptosis (22,(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). Initially, Rab25 was hypothesized to be associated with epithelial cancer, following reports that Rab25 is one of 6 Rab proteins that are upregulated in hepatocellular carcinoma (17).…”

“…Initially, Rab25 was hypothesized to be associated with epithelial cancer, following reports that Rab25 is one of 6 Rab proteins that are upregulated in hepatocellular carcinoma (17). Subsequently, Rab25 was identified as a driver of the 1q22 amplicon, which is frequently amplified in ovarian cancer (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). In a separate study, Rab25 expression was also shown to be correlated with histological grade and it was defined as an androgen response gene in ovarian cancer (36).…”

“…Although data on the involvement of the Rab25 in proliferation, survival, apoptotic signaling, angiogenesis, invasion and metastasis are available, to the best of our knowledge there is no evidence of the precise molecular mechanisms underlying its effects. One study has suggested that it affects TIMP1-associated tumor growth and angiogenesis (39), while another reported that Rab25 is a regulator of cellular bioenergetics in cancer (40 (32) reported that Rab25 functions as a tumor suppressor in HNSCC. In their study, the expression of Rab25 in vitro and in vivo was measured, in association with invasion and metastasis in HNSCC, and it was concluded that downregulation of Rab25 is associated with invasion and metastasis in this disease.…”

The role of endocytic Rab GTPases in regulation of growth factor signaling and the migration and invasion of tumor cells

“…76,77 Similarly Rab25 has differing expression levels with increased expression in estrogen and progesterone receptor positive breast cancer, 78 and suppression in colon and head and neck tumors. 79,80 Down-regulation of Rab38 may be associated with metastasis in melanoma. 81 In gastric cancer, other Rabs have been implicated such as Rab32, Rab34, and Rab40C of which hypermethylation of the Rab32 gene led to downregulation in the tumor 82 and conversely suppression of specific miRNAs; miR-9 and let-7a promoted the efflux of Rab34 and Rab40c expression.…”