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Lactotransferrin Downregulation Serves as a Potential Predictor for the Therapeutic Effectiveness of mTOR Inhibitors in the Metastatic Clear Cell Renal Cell Carcinoma without PTEN Mutation.

ABSTRACT: Approximately 30% of clear cell renal cell carcinoma (ccRCC) patients develop metastatic spread at the first diagnosis. Therefore, identifying a useful biomarker to predict ccRCC metastasis or therapeutic effectiveness in ccRCC patients is urgently needed. Previously, we demonstrated that lactotransferrin (LTF) downregulation enhanced the metastatic potential of ccRCC. Here, we show that LTF expression conversely associates with the mTORC1 activity as simulated by gene set enrichment analysis (GSEA). Moreover, Western blot analyses revealed that the LTF knockdown promoted, but the inclusion of recombinant human LTF protein suppressed, the phosphorylation of Akt/mTOR proteins in the detected ccRCC cells. Kaplan-Meier analyses demonstrated that the signature of combining an upregulated mTORC1 activity with a downregulated LTF expression referred to a worse overall and progression-free survival probabilities and associated with distant cancer metastasis in TCGA ccRCC patients. Furthermore, we found that the LTF-suppressed Akt/mTOR activation triggered an increased formation of autophagy in the highly metastatic ccRCC cells. The addition of autophagy inhibitor 3-methyadenine restored the LTF-suppressed cellular migration ability of highly metastatic ccRCC cells. Receiver operating characteristic (ROC) analyses showed that the expression of the LTF and MTORC1 gene set, not the autophagy gene set, could be the useful biomarkers to predict 5-year overall survival rate and cancer progression in ccRCC patients. Significantly, the signature of combining mTORC1 upregulation and LTF downregulation was shown as an independent prognostic factor in a multivariate analysis under the progression-free survival condition using the TCGA ccRCC database. Finally, the treatment with mTOR inhibitor rapamycin predominantly reduced the formation of autophagy and ultimately mitigated the cellular migration ability of ccRCC cells with LTF knockdown. Our findings suggest that LTF downregulation is a biomarker for guiding the use of mTOR inhibitors to combat metastatic ccRCC in the clinic.

SUBMITTER: Zheng JQ

PROVIDER: S-EPMC8698394 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundChromosomal instability (CIN) is a cancer hallmark and it is difficult to directly measure its phenotype, while a CIN25 gene signature was established to do so in several cancer types. However, it is currently unclear whether there exists this signature in clear cell renal cell carcinoma (ccRCC), and if so, which biological and clinical implications it has.MethodsTranscriptomic profiling was performed on 10 ccRCC tumors and matched renal non-tumorous tissues (NTs) for CIN25 signature analyses. TCGA and E-MBAT1980 ccRCC cohorts were analyzed for the presence of CIN25 signature, CIN25 score-based ccRCC classification, and association with molecular alterations and overall or progression-free survival (OS or PFS). IMmotion150 and 151 cohorts of ccRCC patients treated with Sunitinib were analyzed for the CIN25 impact on Sunitinib response and survival.ResultsThe transcriptomic analysis of 10 patient samples showed robustly upregulated expression of the CIN25 signature genes in ccRCC tumors, which were further confirmed in TCGA and E-MBAT1980 ccRCC cohorts. Based on their expression heterogeneity, ccRCC tumors were categorized into CIN25-C1 (low) and C2 (high) subtypes. The CIN25-C2 subtype was associated with significantly shorter patient OS and PFS, and characterized by increased telomerase activity, proliferation, stemness and EMT. The CIN25 signature reflects not only a CIN phenotype, but also levels of the whole genomic instability including mutation burden, microsatellite instability and homologous recombination deficiency (HRD). Importantly, the CIN25 score was significantly associated with Sunitinib response and survival. In IMmotion151 cohort, patients in the CIN25-C1 group exhibited 2-fold higher remission rate than those in the CIN25-C2 group (P = 0.0004) and median PFS in these two groups was 11.2 and 5.6 months, respectively (P = 7.78E-08). Similar results were obtained from the IMmotion150 cohort analysis. Higher EZH2 expression and poor angiogenesis, well characterized factors leading to Sunitinib resistance, were enriched in the CIN25-C2 tumors.ConclusionThe CIN25 signature identified in ccRCC serves as a biomarker for CIN and other genome instability phenotypes and predicts patient outcomes and response to Sunitinib treatment. A PCR quantification is enough for the CIN25-based ccRCC classification, which holds great promises in clinical routine application.

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Lactotransferrin Downregulation Serves as a Potential Predictor for the Therapeutic Effectiveness of mTOR Inhibitors in the Metastatic Clear Cell Renal Cell Carcinoma without PTEN Mutation.

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