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Research Paper|Volume 15, Issue 17|pp 8908—8929

TIMP1 shapes an immunosuppressive microenvironment by regulating anoikis to promote the progression of clear cell renal cell carcinoma

Qiang Li1,2, Kai Wei4, Xi Zhang3, Yang Lv2, Miao Li1, Chenchao Zhou1, Shifeng Su3, Daorong Hou6, Jianquan Hou1,5
  • 1Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
  • 2Department of Urology, The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University, Suzhou 215228, China
  • 3The State Key Lab of Reproductive, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
  • 4Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
  • 5Department of Urology, Dushu Lake Hospital Affiliated to Soochow University, Suzhou 215000, China
  • 6Key Laboratory of Model Animal Research, Animal Core Facility of Nanjing Medical University, Nanjing Medical University, Nanjing 211166, China
* Equal contribution
Received: May 12, 2023Accepted: July 19, 2023Published: September 8, 2023
https://doi.org/10.18632/aging.205005

Copyright: © 2023 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Background: The association between ccRCC and Anoikis remains to be thoroughly investigated.

Methods: Anoikis-related clusters were identified using NMF. To identify prognostic anoikis-related genes (ARGs) and establish an optimal prognostic model, univariate Cox and LASSO regression were employed. The E-MTAB-1980 cohort was utilized for external validation. Multiple algorithms were used to evaluate the immune properties of the model. GO, KEGG and GSVA analyses were employed to analyze biological pathway functions. qRT-PCR was employed to measure RNA levels of specific genes. Cell Counting Kit-8, wound healing, and Transwell chamber assays were performed to determine changes in the proliferative and metastatic abilities of A498 and 786-O cells.

Results: Based on the expression of 21 prognostic ARGs, we constructed anoikis-related clusters with different prognostic and immune characteristics. The cluster A1 showed a worse prognosis, higher infiltration of immunosuppressive cells and enrichment of several oncogenic pathways. We also calculated the Anoikis Index (AI). Patients in high AI group had a worse prognosis, higher infiltration of immunosuppressive cells and higher expression of immunosuppressive checkpoints. TIMP1 exerted a tumor-promoting role in ccRCC and was significantly associated with immunosuppressive cells and checkpoints. The downregulation of TIMP1 negatively regulated ccRCC cell proliferation and metastasis.

Conclusions: ARGs played crucial roles in tumorigenesis and progression and were positively associated with a poor prognosis. AI had great accuracy in predicting the prognosis and immune characteristics of ccRCC patients. TIMP1 was significantly associated with clinicopathological variables and the immunosuppressive microenvironment, which could be exploited to design novel immunotherapies for ccRCC patients.