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

Jing Quan Zheng, Che Hsuan Lin, Hsun Hua Lee, Wen Ke Wang, Yiu Shun Tong, Kang Yun Lee, Hui Wen Chiu*, Yuan Feng Lin*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

6 Scopus citations

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.

Original languageEnglish
Article number1896
JournalBiomedicines
Volume9
Issue number12
DOIs
StatePublished - 12 2021
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Autophagy
  • LTF
  • MTOR
  • Metastasis
  • Renal cell carcinoma

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