Fig. 8: KIMAT1 silencing halts tumor growth in vivo while its OE promotes tumorigenesis and distant metastases.

a Tumor volume of IC11LC13 PDX mice treated by intravenous injections with vehicle (Ctrl) or GpR-KIMAT1 (Error bars represent mean ± S.D, p value by a two-tailed Student’s t test.). Ctrl n = 6, KIMAT1 KD n = 3. *0.01194 and 0.002246. b Representative IHC images of KRAS and Ki67 levels in lungs of mice treated with KIMAT1 GpRs compared to controls. c Representative lungs and livers from NSG mice percutaneously injected into the left lateral thorax with H1299luc + cells stably expressing KIMAT1 or an empty vector. Tumors are evidenced by dashed lines. n = 7. d Representative examples of H&E staining of livers, kidneys and lungs from mice injected with KIMAT1 stable cells as in c. A single isolated tumor cell is present (arrow head) in the liver of a H1299/Ev mouse. No neoplastic cell is present in a H1299/Ev mouse kidney, whereas a small neoplastic lesion is observed within its lung (under the dashed line). Mice injected with H1299/KIMAT1 cells presented diffuse metastatic infiltration in the livers, peri-renal fat tissue (under the dashed line) and the lungs (mostly entirely substituted by neoplastic tissue). Original magnifications 0.6× and 40×; scale bar, 50 μm. n = 7. e Representative H&E and KRAS staining of lung sections from NSG mice percutaneously injected with DHX9 KO or NPM1 KO cells. Original magnifications 0.6× and 40×; scale bar, 50 μm. n = 8. f Schematics depicting KIMAT1’s mechanism of action. KRAS amplification activates KIMAT1 via MYC-mediated transcription. KIMAT1 binds to and stabilizes DHX9 and NPM1, which promote the processing of oncogenic miRNAs sustaining the KRAS signalling in a positive feedback loop. p21 antagonizes the binding between DDX5 and DHX9 and between DDX5 and NPM1 fostering the processing of tumor suppressor miRNAs which halt KRAS signalling and EMT.