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This mitogenic response is directly induced by upregulation of IGF1R transcription and occurs independently of VHL's role in suppressing the hypoxia pathway.45–47 Despite of the clear association between activation of renal IGF-1 signaling and RCC occurrence and progression, low circulating IGF-1 levels have been linked to an increased risk of renal cancer, particularly in a cohort of male smokers after at least five years of follow-up.48 This finding raises doubts about the utility of circulating IGF-1 as a reliable biomarker for renal cancer risk