Research Article: PBRM1 regulates proliferation and the cell cycle in renal cell carcinoma through a chemokine/chemokine receptor interaction pathway

Date Published: August 28, 2017

Publisher: Public Library of Science

Author(s): HongKai Wang, YuanYuan Qu, Bo Dai, Yao Zhu, GuoHai Shi, YiPing Zhu, YiJun Shen, HaiLiang Zhang, DingWei Ye, Aamir Ahmad.

http://doi.org/10.1371/journal.pone.0180862

Abstract

PBRM1 is a novel tumor suppressor gene that can inhibit cancer cell proliferation and predict the outcome of renal cell carcinoma (RCC), but its biological role needs further elucidation. We examined expression of the PBRM1 gene in RCC cell lines and the effect of PBRM1 on cell proliferation and cell cycle in RCC ACHN cells. Microarray processing and analysis was used to explore novel pathways involved in tumorigenesis related to PBRM1 knockdown. PBRM1 was expressed at high levels in RCC ACHN cells and lentivirus-mediated PBRM1 knockdown in these cells caused an increase in the proportion of cells in S phase of the cell cycle and promoted in vitro proliferation and migration. In vivo experiments showed that downregulation of PBRM1 promoted tumorigenesis in nude mice. In pathway gene chip analysis, the chemokine/chemokine receptor interaction pathway showed the greatest difference in gene expression upon PBRM1 knockdown. Protein levels of IL6ST and CCL2 were increased, whereas levels of interleukin (IL)-8, IL-6, and CXCL2 were decreased, in knockdown cells. Re-expression of IL-8 in PBRM1 knockdown ACHN cells could significantly decrease cell proliferation/migration and induced cell arrest in the G2/M phase. These findings indicate that PBRM1 alters cell cycle progression and inhibits proliferation and migration of ACHN cells through the chemokine/chemokine receptor pathway.

Partial Text

Renal cell carcinoma (RCC) is the most common type of cancer in the kidney and accounts for approximately 3% of all adult malignancies[1]. Among RCCs, clear cell RCC (ccRCC) is the most common subtype, accounting for approximately 70%–75% of cases[2], and is more likely to present with advanced T stage, metastatic disease, and higher grade[3]. Alteration in the von Hippel-Lindau (VHL) gene is the hallmark of ccRCC; however, inactivation of VHL has not been found to consistently correlate with prognostic features of ccRCC[4]. Recently, exome sequencing has unveiled additional genes that are mutated in ccRCC, including PBRM1, BAP1, and SETD2[5]. As the second most frequently mutated gene after VHL, the role of PBRM1 in ccRCC tumorigenesis is of great interest.

Clear cell renal cell carcinoma accounts for 70%–80% of all kidney cancers, and is known to exhibit very frequent inactivation of the von Hippel-Lindau gene (VHL) as a result of either somatic mutations or epigenetic alterations[10]. In addition to VHL, sequencing studies have revealed that truncating mutations in PBRM1, which encodes a subunit of the ATP-dependent chromatin remodeling complex of SWI/SNF, are present in more than 40% of ccRCCs[5]. Other frequently mutated genes in ccRCC are SETD2, TCEB1, BAP1, and KDM5C[11]. It is interesting that PBRM1, BAP1, and SETD2 are all located at chromosome 3p, close to the 3p25 locus, indicating that these tumor suppressors might be functionally linked. As PBRM1 is the second most frequently mutated gene after VHL, its interaction with other mutated genes and its role in ccRCC tumorigenesis and progression are areas of great interest.

PBRM1 may alter cell cycle progression and inhibit proliferation and invasion of ACHN cells through the chemokine/chemokine receptor pathway. Understanding the contribution of PBRM1 dysregulation and its associated pathways to clinical disease progression and outcome are important future areas of renal cancer research.

All experimental protocols were approved by the Review Committee for the Use of Human or Animal Subjects of Fudan University and the experimental methods were performed in accordance with relevant guidelines and regulations.

 

Source:

http://doi.org/10.1371/journal.pone.0180862

 

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