Rab1A promotes cancer metastasis and radioresistance through activating GSK-3β/Wnt/β-catenin signaling in nasopharyngeal carcinoma

Abstract

Many articles have reported that Rab1A was overexpressed in a variety of human cancers and involved in tumor progression and metastasis. However, the biological function and molecular mechanism of Rab1A in nasopharyngeal carcinoma (NPC) remained unknown until now. Here we found that Rab1A overexpression is a common event and was positively associated with distant metastasis and poor prognosis of NPC patients. Functionally, Rab1A depletion inhibited the migration and EMT phenotype of NPC cells, whereas Rab1A overexpression led to the opposite effect. Furthermore, we reveal an important role for Rab1A protein in the induction of radioresistance via regulating homologous recombination (HR) signaling pathway. Mechanistically, Rab1A activated Wnt/β-catenin signaling by inhibiting the activity of GSK-3β via phosphorylation at Ser9. Then Wnt/β-catenin signaling induced NPC cells radioresistance and metastasis through nuclear translocation of β-catenin and transcription upregulation of HR pathway-related and EMT-related genes expression. In general, this study shows that Rab1A may serve as a potential biomarker for predicting prognosis in NPC patients. Targeting Rab1A and Wnt/β-catenin signaling may hold promise to overcome NPC radioresistance.

Rab1A promotes cell proliferation and migration by upregulating Gli1 in colorectal cancer

“…EMT plays a crucial role in tumor cell metastasis, which is accompanied by upregulation of mesenchymal-associated markers (such as Vimentin) and downregulation of epithelial-associated markers (such as E-cadherin) 29 . In this study, we found for the first time that Rab1A promoted EMT progress in CRC cells evidenced by the facts that Rab1A knockdown increased E-cadherin expression and decreased Vimentin expression whereas Rab1A overexpression did the opposite, which is in accordance with the previous study in nasopharyngeal carcinoma 11 .…”

“…In cancers, the role of Rab1A is contentious and it could be either oncogenic or tumor suppressive. Rab1A was described as an oncogene in gastric cancer 8 , nasopharyngeal carcinoma 11 , breast cancer 12 , lung cancer 13 and hepatocellular carcinoma 14 . On the other hand, Rab1A expression was reduced and played anti-carcinogenic roles in androgen-independent prostate cancer 15 .…”

“…It has been reported that Rab1A protein is involved in mediating signal transduction 9 and cell migration 10 . Recently, Rab1A has been described as an oncogene in multiple types of cancers, such as gastric cancer 8 , nasopharyngeal carcinoma 11 , breast cancer 12 , lung cancer 13 and hepatocellular carcinoma 14 . On the other hand, it was reported that Rab1A expression was reduced in androgen-independent prostate cancer and Rab1A depletion enhanced the proliferation ability of prostate cancer cells 15 .…”

Targeting Epithelial-to-Mesenchymal Transition in Radioresistance: Crosslinked Mechanisms and Strategies

“…Activation of Wnt/b-catenin signaling is important in regulating stemness, metastasis, and proliferation of malignant tumors, and recent studies have also shown that it is implicated in tumor radioresistance by inducing EMT (70,71). Bastos LG et al (11) reported that Wnt/b-catenin signaling could promote the radioresistance and metastasis of NPC cells by increasing nuclear translocation of b-catenin and transcriptional upregulation of EMTrelated genes expression. Another study reported that Wnt/bcatenin pathway triggered the acquisition of EMT phenotype by modulating the activity of aldehyde dehydrogenase (ALDH), thus improving the resistance of prostate cancer progenitor cells to irradiation (12).…”

ER resident protein 44 promotes malignant phenotype in nasopharyngeal carcinoma through the interaction with ATP citrate lyase

“…It occurs accompanied with the loss of epithelial markers the gain of mesenchymal markers [ 36 ]. Studies have reported that some oncogenes could decrease the expression of E-cadherin and induce mesenchymal phenotypes to promote NPC metastasis [ 37 , 38 ]. In colon cancer, ACLY was highly expressed and could promote cell metastasis, especially the process of EMT [ 39 ].…”