FKBP51 promotes invasion and migration by increasing the autophagic degradation of TIMP3 in clear cell renal cell carcinoma

Shaowei Mao,Qinghua Xia,Sijia Huang,Yueran Zhao,Wenqi Zhou,Muyun Wei,Jie Tan,Di Zhang,Luan Chen,Yunpeng Chu,Rongxiu Li,Hengwei Qin,Shengying Qin

doi:10.1038/s41419-021-04192-8

Shaowei Mao, Qinghua Xia + Show 11 more

Open Access

https://doi.org/10.1038/s41419-021-04192-8

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Abstract

The occurrence of metastasis is a serious risk for renal cell carcinoma (RCC) patients. In order to develop novel therapeutic approaches to control the progression of metastatic RCC, it is of urgent need to understand the molecular mechanisms underlying RCC metastasis and identify prognostic markers of metastatic risk. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) have been known to be closely associated with extracellular matrix (ECM) turnover, which plays a highly active role in tumor metastasis. Recent studies have shown that immunophilin FK-506-binding protein 51 (FKBP51) may be important for the regulation of ECM function, and exert effects on the invasion and migration of tumor cells. However, the mechanisms underlying these activities remain unclear. The present study detected the role of FKBP51 in clear cell renal cell carcinoma (ccRCC), the most common subtype of RCC, and found that FKBP51 significantly promotes ccRCC invasion and migration by binding with the TIMP3, connecting TIMP3 with Beclin1 complex and increasing autophagic degradation of TIMP3. Given the important roles that TIMPs/MMPs play in ECM regulation and remodeling, our findings will provide new perspective for future investigation of the regulation of metastasis of kidney cancer and other types of cancer.

Highlights

Renal cell carcinoma (RCC) is one of the most common cancers globally, with 403,262 new cases having been diagnosed and175,098 people having died from the disease in 2018 [1]
Immunohistochemistry (IHC) staining of FK-506-binding protein 51 (FKBP51) in 70 Clear-cell renal cell carcinoma (ccRCC) samples and 49 adjacent normal tissues showed that the protein levels of FKBP51 were significantly higher in ccRCC tissues than in adjacent nontumorous tissues (ANTs) (p < 0.001, Fig. 1d, e), and upregulated in patients who developed distant metastasis compared to patients without distant metastasis (p < 0.05, Fig. 1f and Table 1)
CHX + FKBP51) (Fig. 5f), while treatment with MG132 showed no clear influence on the half-life of TIMP3 (Fig. 5g). These results showed that overexpressing FKBP51 increases the autophagic degradation of the TIMP3 protein, and this effect can be blocked by exposure to the autophagy inhibitor, 3-MA

Summary

Introduction

Renal cell carcinoma (RCC) is one of the most common cancers globally, with 403,262 new cases having been diagnosed and175,098 people having died from the disease in 2018 [1]. Renal cell carcinoma (RCC) is one of the most common cancers globally, with 403,262 new cases having been diagnosed and. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that control the degradation of a wide spectrum of extracellular matrix-associated (ECM) and cell surface-associated proteins. MMPs (MMP1–28) are widely expressed during tumor progression and metastasis [4, 5]. Serum levels of MMP7 were significantly increased in metastatic RCC, and high MMP7 levels were independently associated with shorter disease-specific survival [6,7,8]. MMP9 has been indicated to be a negative prognostic factor in RCC [9, 10] and an essential factor for vasculogenic mimicry formation and tumor metastasis in ccRCC [11, 12].

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