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Advances in Nano Research Volume 12, Number 6, June 2022 , pages 639-652 DOI: https://doi.org/10.12989/anr.2022.12.6.639 |
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P3H4 promotes renal cell carcinoma progression and suppresses antitumor immunity via regulating GDF15-MMP9-PD-L1 axis |
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Shuo Tian, Yan Huang, Dong Lai, Hanfeng Wang, Songliang Du, Donglai Shen, Weihao Chen, Yundong Xuan, Yongliang Lu, Huayi Feng, Xiangyi Zhang, Wenlei Zhao, Chenfeng Wang, Tao Wang, Shengpan Wu, Qingbo Huang, Shaoxi Niu, Baojun Wang, Xin Ma and Xu Zhang
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| Abstract | ||
| The prolyl 3-hydroxylase family member 4 (P3H4), is associated with post-translational modification of fibrillar collagens and aberrantly activated in cancer leading to tumor progression. However, its role in clear cell renal cell carcinoma (ccRCC) is still unknown. Here we reported that P3H4 was highly expressed in renal cancer tissues and significantly positive correlated with poor prognosis. Knockdown of P3H4 inhibited the proliferation, migration and metastasis of renal cancer cells in vitro and in vivo, and also, overexpression of it enhanced the oncogenic process. Mechanistically, P3H4 depletion decreased the levels of GDF15-MMP9 axis and repressed its downstream signaling. Further functional studies revealed that inhibition of GDF15 suppressed renal cancer cell growth and GDF15 recombinant human protein (rhGDF15) supplementation effectively rescued the inhibitory effect induced by P3H4 knockdown. Moreover, decreased levels of MMP9 caused by inhibition of P3H4-GDF15 signaling constrained the expression of PD-L1 and suppression of P3H4 accordingly promoted anti-tumor immunity via stimulating the infiltration of CD4+ and CD8+ T cells in syngeneic mice model. Taken together, our findings firstly demonstrated that P3H4 promotes ccRCC progression by activating GDF15-MMP9-PD-L1 axis and targeting P3H4-GDF15-MMP9 signaling pathway can be a novel strategy of controlling ccRCC malignancy. | ||
| Key Words | ||
| ccRCC; GDF15; immunosuppression; MMP9; P3H4; PD-L1 | ||
| Address | ||
| Shuo Tian, Yan Huang, Dong Lai, Weihao Chen, Yundong Xuan, Yongliang Lu, Huayi Feng and Chenfeng Wang: Chinese PLA Medical School, Beijing 100853, PR China/ Department of Urology, The Third Medical Centre, Chinese PLA General Hospital, Beijing 100853, PR China Hanfeng Wang, Songliang Du, Donglai Shen, Shengpan Wu, Qingbo Huang, Shaoxi Niu, Baojun Wang, Xin Ma and Xu Zhang: Department of Urology, The Third Medical Centre, Chinese PLA General Hospital, Beijing 100853, PR China Xiangyi Zhang: Department of Urology, The Third Medical Centre, Chinese PLA General Hospital, Beijing 100853, PR China/ School of Medicine, Nankai University, Tianjin 300071, PR China | ||