RHBDD1 promotes proliferation, migration, invasion and EMT in renal cell carcinoma via the EGFR/AKT signaling pathway

Li,Mingyang; Cai,Licheng; Wang,Xingyuan; Yu,Yipeng; Jian,Wengang; Bao,Guochang; Gao,Zhiming; Guo,Junsheng; Zhang,Jian; Li,Chunsheng; Zhang,Cheng

doi:10.3892/mmr.2021.12466

RHBDD1 promotes proliferation, migration, invasion and EMT in renal cell carcinoma via the EGFR/AKT signaling pathway

Authors:
- Mingyang Li
- Licheng Cai
- Xingyuan Wang
- Yipeng Yu
- Wengang Jian
- Guochang Bao
- Zhiming Gao
- Junsheng Guo
- Jian Zhang
- Chunsheng Li
- Cheng Zhang
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Affiliations: Department of Urology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China, Department of Urology, Affiliated Hospital of Chifeng University, Chifeng, Inner Mongolia Autonomous Region 024005, P.R. China
Published online on: September 27, 2021 https://doi.org/10.3892/mmr.2021.12466
Article Number: 826
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Renal cell carcinoma (RCC) is a common malignant tumor of the urinary system with a poor prognosis and high mortality rate. The increasing incidence of RCC poses a serious threat to human health. It is well‑documented that rhomboid domain‑containing protein 1 (RHBDD1) plays a vital role in cancer progression. The present study was designed to identify the biological functions of RHBDD1 in RCC and investigate the underlying regulatory mechanism, aiming to explore the novel molecular therapeutic targets for RCC. The protein and mRNA expression levels of RHBDD1 in normal renal tubule epithelium and human RCC cell lines were analyzed using western blotting and reverse transcription‑quantitative PCR. Cell proliferation was determined using Cell Counting Kit‑8 assays. Wound healing and Transwell assays were performed to determine cell migration and invasion, respectively. In addition, key proteins related to migration, invasion and epithelial‑mesenchymal transition (EMT), such as matrix metalloproteinase (MMP)2, MMP9, MMP13, E‑cadherin, N‑cadherin, vimentin and Slug, were analyzed using western blotting. In addition, the EGFR/AKT signaling pathway was further studied using western blotting to determine the potential molecular mechanism. The results of the present study revealed that RHBDD1 expression levels were significantly upregulated in RCC cell lines. The knockdown of RHBDD1 inhibited cell proliferation, migration, invasion and EMT, while the overexpression of RHBDD1 promoted cell proliferation, migration, invasion and EMT in RCC. In addition, the knockdown of RHBDD1 suppressed the activation of the EGFR/AKT signaling pathway, while the overexpression of RHBDD1 activated the EGFR/AKT signaling pathway. Moreover, these stimulatory effects of RHBDD1 overexpression on RCC progression and the EGFR/AKT signaling pathway were partly reversed by gefitinib, an EGFR inhibitor. In conclusion, the findings of the present study suggested that RHBDD1 may be a crucial regulator of RCC by modulating the EGFR/AKT signaling pathway. The present study may provide a theoretical basis and potential targets for RCC treatment.

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1	Chen S, Wang Y, Xiong Y, Peng T, Lu M, Zhang L and Guo Z: Wild-type IDH1 inhibits the tumor growth through degrading HIF-α in renal cell carcinoma. Int J Biol Sci. 17:1250–1262. 2021. View Article : Google Scholar : PubMed/NCBI
2	Huang T, Wang X, Yang X, Ji J, Wang Q, Yue X and Dong Z: long non-coding RNA DUXAP8 enhances renal cell carcinoma progression via downregulating miR-126. Med Sci Monit. 24:7340–7347. 2018. View Article : Google Scholar : PubMed/NCBI
3	Cohen HT and McGovern FJ: Renal-cell carcinoma. N Engl J Med. 353:2477–2490. 2005. View Article : Google Scholar : PubMed/NCBI
4	Zhu H, Wang Z, Xu Q, Zhang Y, Zhai Y, Bai J, Liu M, Hui Z and Xu N: Inhibition of STAT1 sensitizes renal cell carcinoma cells to radiotherapy and chemotherapy. Cancer Biol Ther. 13:401–407. 2012. View Article : Google Scholar : PubMed/NCBI
5	Teng ZY, Cheng XL, Cai XT, Yang Y, Sun XY, Xu JD, Lu WG, Chen J, Hu CP, Zhou Q, et al: Ancient Chinese Formula Qiong-Yu-Gao Protects Against Cisplatin-Induced Nephrotoxicity Without Reducing Anti-tumor Activity. Sci Rep. 5:155922015. View Article : Google Scholar : PubMed/NCBI
6	Flippot R, Escudier B and Albiges L: Immune Checkpoint Inhibitors: Toward New Paradigms in Renal Cell Carcinoma. Drugs. 78:1443–1457. 2018. View Article : Google Scholar : PubMed/NCBI
7	Zhong Y, Lu YT, Sun Y, Shi ZH, Li NG, Tang YP and Duan JA: Recent opportunities in matrix metalloproteinase inhibitor drug design for cancer. Expert Opin Drug Discov. 13:75–87. 2018. View Article : Google Scholar : PubMed/NCBI
8	Liu QH, Wang Y, Yong HM, Hou PF, Pan J, Bai J and Zheng JN: XRCC1 serves as a potential prognostic indicator for clear cell renal cell carcinoma and inhibits its invasion and metastasis through suppressing MMP-2 and MMP-9. Oncotarget. 8:109382–109392. 2017. View Article : Google Scholar : PubMed/NCBI
9	Liang F, Wang YG and Wang C: Metformin inhibited growth, invasion and metastasis of esophageal squamous Cell Carcinoma in vitro and in vivo. Cell Physiol Biochem. 51:1276–1286. 2018. View Article : Google Scholar : PubMed/NCBI
10	Tsai JH, Donaher JL, Murphy DA, Chau S and Yang J: Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell. 22:725–736. 2012. View Article : Google Scholar : PubMed/NCBI
11	Zhang P, Sun Y and Ma L: ZEB1: At the crossroads of epithelial-mesenchymal transition, metastasis and therapy resistance. Cell Cycle. 14:481–487. 2015. View Article : Google Scholar : PubMed/NCBI
12	Pan G, Liu Y, Shang L, Zhou F and Yang S: EMT-associated microRNAs and their roles in cancer stemness and drug resistance. Cancer Commun (Lond). 41:199–217. 2021. View Article : Google Scholar : PubMed/NCBI
13	Chuang MJ, Sun KH, Tang SJ, Deng MW, Wu YH, Sung JS, Cha TL and Sun GH: Tumor-derived tumor necrosis factor-alpha promotes progression and epithelial-mesenchymal transition in renal cell carcinoma cells. Cancer Sci. 99:905–913. 2008. View Article : Google Scholar : PubMed/NCBI
14	Liao BC, Lin CC and Yang JC: Second and third-generation epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer. Curr Opin Oncol. 27:94–101. 2015. View Article : Google Scholar : PubMed/NCBI
15	Singh D, Attri BK, Gill RK and Bariwal J: Review on EGFR Inhibitors: Critical Updates. Mini Rev Med Chem. 16:1134–1166. 2016. View Article : Google Scholar : PubMed/NCBI
16	Wang J, Xu H, Cheng X, Yang J, Yan Z, Ma H, Zhao Y, Ommati MM, Manthari RK and Wang J: Calcium relieves fluoride-induced bone damage through the PI3K/AKT pathway. Food Funct. 11:1155–1164. 2020. View Article : Google Scholar : PubMed/NCBI
17	Manning BD and Toker A: AKT/PKB Signaling: Navigating the Network. Cell. 169:381–405. 2017. View Article : Google Scholar : PubMed/NCBI
18	Brown JS and Banerji U: Maximising the potential of AKT inhibitors as anti-cancer treatments. Pharmacol Ther. 172:101–115. 2017. View Article : Google Scholar : PubMed/NCBI
19	Liu L, Miao L, Liu Y, Qi A, Xie P, Chen J and Zhu H: S100A11 regulates renal carcinoma cell proliferation, invasion, and migration via the EGFR/Akt signaling pathway and E-cadherin. Tumour Biol. 39:10104283177053372017. View Article : Google Scholar : PubMed/NCBI
20	Wang Y, Guan X, Fok KL, Li S, Zhang X, Miao S, Zong S, Koide SS, Chan HC and Wang L: A novel member of the Rhomboid family, RHBDD1, regulates BIK-mediated apoptosis. Cell Mol Life Sci. 65:3822–3829. 2008. View Article : Google Scholar : PubMed/NCBI
21	Zhao C, Ling X, Li X, Hou X and Zhao D: MicroRNA-138-5p inhibits cell migration, invasion and EMT in breast cancer by directly targeting RHBDD1. Breast Cancer. 26:817–825. 2019. View Article : Google Scholar : PubMed/NCBI
22	Huang C, Ji X, Peng Y, Wu M, Wu W, Luo Y, Cheng G and Zhu Y: Silencing of rhomboid domain containing 1 to inhibit the metastasis of human breast cancer cells in vitro. Iran J Basic Med Sci. 21:1161–1166. 2018.PubMed/NCBI
23	Song W, Liu W, Zhao H, Li S, Guan X, Ying J, Zhang Y, Miao F, Zhang M, Ren X, et al: Rhomboid domain containing 1 promotes colorectal cancer growth through activation of the EGFR signalling pathway. Nat Commun. 6:80222015. View Article : Google Scholar : PubMed/NCBI
24	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
25	Kitano H, Kitadai Y, Teishima J, Yuge R, Shinmei S, Goto K, Inoue S, Hayashi T, Sentani K, Yasui W, et al: Combination therapy using molecular-targeted drugs modulates tumor microenvironment and impairs tumor growth in renal cell carcinoma. Cancer Med. 6:2308–2320. 2017. View Article : Google Scholar : PubMed/NCBI
26	Hawkins R, Fife K, Hurst M, Wang M, Naicker N, Nolasco S, Eisen T, Matakidou A and Gordon J: Treatment patterns and health outcomes in metastatic renal cell carcinoma patients treated with targeted systemic therapies in the UK. BMC Cancer. 20:6702020. View Article : Google Scholar : PubMed/NCBI
27	Liu XN, Tang ZH, Zhang Y, Pan QC, Chen XH, Yu YS and Zang GQ: Lentivirus-mediated silencing of rhomboid domain containing 1 suppresses tumor growth and induces apoptosis in hepatoma HepG2 cells. Asian Pac J Cancer Prev. 14:5–9. 2013. View Article : Google Scholar : PubMed/NCBI
28	Zhang M, Miao F, Huang R, Liu W, Zhao Y, Jiao T, Lu Y, Wu F, Wang X, Wang H, et al: RHBDD1 promotes colorectal cancer metastasis through the Wnt signaling pathway and its downstream target ZEB1. J Exp Clin Cancer Res. 37:222018. View Article : Google Scholar : PubMed/NCBI
29	Souza JL, Martins-Cardoso K, Guimarães IS, de Melo AC, Lopes AH, Monteiro RQ and Almeida VH: Interplay Between EGFR and the Platelet-Activating Factor/PAF Receptor Signaling Axis Mediates Aggressive Behavior of Cervical Cancer. Front Oncol. 10:5572802020. View Article : Google Scholar : PubMed/NCBI
30	Zhou Q, Huang T, Jiang Z, Ge C, Chen X, Zhang L, Zhao F, Zhu M, Chen T, Cui Y, et al: Upregulation of SNX5 predicts poor prognosis and promotes hepatocellular carcinoma progression by modulating the EGFR-ERK1/2 signaling pathway. Oncogene. 39:2140–2155. 2020. View Article : Google Scholar : PubMed/NCBI
31	Yin L, Gao S, Shi H, Wang K, Yang H and Peng B: TIP-B1 promotes kidney clear cell carcinoma growth and metastasis via EGFR/AKT signaling. Aging (Albany NY). 11:7914–7937. 2019. View Article : Google Scholar : PubMed/NCBI