Chromosomal translocation-derived aberrant Rab22a drives metastasis of osteosarcoma.

Abstract

Osteosarcoma is a type of aggressive malignant bone tumour that frequently metastasizes to lungs, resulting in poor prognosis. However, the molecular mechanisms of lung metastasis of osteosarcoma remain poorly understood. Here we identify exon-intron fusion genes in osteosarcoma cell lines and tissues. These fusion genes are derived from chromosomal translocations that juxtapose the coding region for amino acids 1-38 of Rab22a (Rab22a1-38) with multiple inverted introns and untranslated regions of chromosome 20. The resulting translation products, designated Rab22a-NeoFs, acquire the ability to drive lung metastasis of osteosarcoma. The Rab22a1-38 moiety governs the function of Rab22a-NeoFs by binding to SmgGDS-607, a GTP-GDP exchange factor of RhoA. This association facilitates the release of GTP-bound RhoA from SmgGDS-607, which induces increased activity of RhoA and promotes metastasis. Disrupting the interaction between Rab22a-NeoF1 and SmgGDS-607 with a synthetic peptide prevents lung metastasis in an orthotopic model of osteosarcoma. Our findings may provide a promising strategy for a subset of osteosarcoma patients with lung metastases.

• Authors: Dan Liao, Li Zhong, Junqiang Yin, Cuiling Zeng, Xin Wang, Xingchuan Huang, Jinna Chen, Hong Zhang, Ruhua Zhang, Xin-Yuan Guan, Xintao Shuai, Jianhua Sui, Song Gao, Wuguo Deng, Yi-Xin Zeng, Jing-Nan Shen, Jian Chen, Tiebang Kang
• Journal: Nature cell biology (Nat Cell Biol) Vol. 22 Issue 7 Pg. 868-881 (07 2020) ISSN: 1476-4679 [Electronic] England
• PMID: 32483387 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• RAB22A protein, human
• rab GTP-Binding Proteins

Topics

• Adult
• Animals
• Apoptosis
• Biomarkers, Tumor (genetics, metabolism)
• Bone Neoplasms (genetics, metabolism, pathology)
• Cell Movement
• Cell Proliferation
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Lung Neoplasms (genetics, metabolism, secondary)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred NOD
• Mice, Nude
• Mice, SCID
• Osteosarcoma (genetics, metabolism, pathology)
• Prognosis
• Translocation, Genetic
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays
• Young Adult
• rab GTP-Binding Proteins (genetics, metabolism)