Abstract
Cervical cancer is the most common gynecological malignancy in the world; however, the survival rates of advanced-stage and recurrent cervical cancer patients remain poor. The multifaced protein insulin-like growth factor 2 receptor (IGF2R) has various ligands, represented as IGF-2 and mannose-6-phosphate (M6P)-tagged proteins. Regarding its antagonistic activity as an IGF1R signal, IGF2R is currently considered a tumor suppressor gene, whereas its significance as an M6P receptor is still unclear. Here, on the basis of transcriptome analysis of TCGA and GEO open datasets, we show that IGF2R is upregulated and correlated with poor prognosis in cervical cancer. Several experiments using cervical cancer cell lines revealed that IGF2R depletion induced apoptosis, decreased cell viability, and increased vulnerability to certain anticancer drug cisplatin. In contrast to its negligible impact in IGF1R signaling, loss of IGF2R disrupted the Golgi-to-lysosome transport of M6P-tagged cathepsins, resulting in decreased lysosomal activity, with their abnormal accumulation and dysfunction of both autophagy and mitophagy, which cause the accumulation of misfolded proteins and production of reactive oxygen species. Taken together, IGF2R has an oncogenic role through transportation of M6P-tagged cargo in cervical cancer and can be used as a predictive biomarker for prognostic classification.
Highlights
Cervical cancer is the most common gynecological malignancy in the world
insulin-like growth factor 2 receptor (IGF2R) is a poor prognostic biomarker in patients with cervical cancer Thirteen candidate genes were identified as being highly expressed in poor survivors vis-à-vis good survivors (Fig. 1a)
A multi-omics analysis revealed that genetic alterations in IGF2R tended to be mutually exclusive of those in insulin-like growth factor 1 receptor (IGF1R) but not of those in either insulin receptor (INSR) or their ligands (Supplementary Fig. S1a)
Summary
Cervical cancer is the most common gynecological malignancy in the world. Approximately 311,000 of affected patients died in 2018, accounting for 7.5% of cancer-related deaths worldwide[1]. The cation-independent mannose 6-phosphate/insulinlike growth factor 2 receptor (CI-M6P/IGF2R, hereafter IGF2R) is a type-1 transmembrane glycoprotein consisting of a large N-terminal extracytoplasmic domain, which allows it to bind to a wide variety of ligands[4,5,6,7]. It has two major types of ligands: insulin-like growth factor 2 (IGF2) and mannose 6-phosphate (M6P)-labeled glycosylated proteins, both of which have distinct but important roles in normal development and homeostasis in mammals.
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