Abstract
Hematopoietic pre-B cell leukemia transcription factor (PBX)-interacting protein (HPIP) was shown to be crucial during the development and progression of a variety of tumors. However, the role of HPIP in renal cell carcinoma (RCC) is unknown. Here we report that HPIP is upregulated in most RCC patients, positively correlates with tumor size, high Fuhrman grade and preoperative metastasis, and predicts poor clinical outcomes. Mechanistically, we identified casein kinase 1α (CK1α), a critical regulator of tumorigenesis and metastasis, as a novel HPIP-interacting protein. HPIP facilitates RCC cell growth, migration, invasion and epithelial–mesenchymal transition depending on its interaction with CK1α. Activation of mammalian target of rapamycin pathways by HPIP is partly dependent on CK1α and is required for HPIP modulation of RCC cell proliferation and migration. HPIP knockdown suppresses renal tumor growth and metastasis in nude mice through CK1α. Moreover, expression of CK1α is positively correlated with HPIP in RCC samples, and also predicts poor clinical outcome-like expression of HPIP. Taken together, our data demonstrate the critical regulatory role of the HPIP–CK1α interaction in RCC, and suggest that HPIP and CK1α may be potential targets for RCC therapy.
Highlights
Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, responsible for ~ 90–95% of kidney malignancies
Clinical significance of HPIP expression in human RCC samples To investigate the clinical significance of HPIP in RCC, first, we assessed HPIP expression by immunohistochemical staining of tissues consisting of 119 pairs of human RCC tumors and their matched non-tumor renal tissues
As HPIP has been shown to activate Mammalian Target of Rapamycin (mTOR) signaling in liver cancer cells,[6] we investigated whether activation of mTOR signaling is responsible for HPIP modulation of RCC cell proliferation and migration
Summary
Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, responsible for ~ 90–95% of kidney malignancies. Surgical operation remains the most effective treatment for RCC, but up to 30% newly diagnosed patients develop metastasis, with the 5-year survival rate of o 10%, and 20–30% post-surgery treatment cases eventually develop recurrence.[1] As RCC is resistant to traditional chemotherapy, hormonal therapy or radiation therapy, further investigation of the molecular mechanisms underlying RCC tumorigenesis and progression is crucial for individual treatment of RCC. Interacting protein (HPIP), a co-repressor for pre-B-cell leukemia homeobox 1 (PBX1), is known to act as a promoter during tumorigenesis. The role of HPIP in RCC remains unknown. We first investigated the role of HPIP in RCC growth and metastasis both in vitro and in vivo. We identified casein kinase 1α (CK1α), a critical regulator of tumorigenesis and metastasis, as a novel HPIP-interacting protein, linking the oncogenic ability of HPIP to its interaction with
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