Mutant KRAS Mediates circARFGEF2 Biogenesis to Promote Lymphatic Metastasis of Pancreatic Ductal Adenocarcinoma

Authors：Kong, Yao; Luo, Yuming; Zheng, Shangyou; Yang, Jiabin; Zhang, Dingwen; Zhao, Yue; Zheng, Hanhao; An, Mingjie; Lin, Yan; Ai, Le; Diao, Xiayao; Lin, Qing; Chen, Changhao^*; Chen, Rufu^*

Source：Cancer Research, 2023, 83(18): 3077-3094.

DOI：10.1158/0008-5472.CAN-22-3997

• CIRCULAR RNAS
• MECHANISMS
• CELLS

Circular RNAs (circRNA) contribute to cancer stemness, proliferation, and metastasis. The biogenesis of circRNAs can be impacted by the genetic landscape of tumors. Herein, we identified a novel circRNA, circARFGEF2 (hsa_circ_0060665), which was upregulated in KRASG12D pancreatic ductal adenocarcinoma (PDAC) and positively associated with KRASG12D PDAC lymph node (LN) metastasis. CircARFGEF2 overexpression significantly facilitated KRASG12D PDAC LN metastasis in vitro and in vivo. Mechanistically, circARFGEF2 biogenesis in KRASG12D PDAC was significantly activated by the alternative splicing factor QKI-5, which recruited U2AF35 to facilitate spliceosome assembly. QKI-5 bound the QKI binding motifs and neighboring reverse complement sequence in intron 3 and 6 of ARFGEF2 pre-mRNA to facilitate circARFGEF2 biogenesis. CircARFGEF2 sponged miR-1205 and promoted the activation of JAK2, which phosphorylated STAT3 to trigger KRASG12D PDAC lymphangiogenesis and LN metastasis. Importantly, circARFGEF2 silencing significantly inhibited LN metastasis in the KrasG12D/+Trp53R172H/+Pdx-1-Cre (KPC) mouse PDAC model. These findings provide insight into the mechanism and metastasis-promoting function of mutant KRAS-mediated circRNA biogenesis.

• Institution
  中山大学; 中国医学科学院; 中国医学科学院北京协和医院; 广东省心血管病研究所; 南方医科大学; 1; 广东省人民医院