Reactive stroma component COL6A1 is upregulated in castration-resistant prostate cancer and promotes tumor growth.

Yi-Ping Zhu,Yi-Jun Shen,Gui-Ming Zhang,Fang-Ning Wan,Hong-Kai Wang,Ding-Wei Ye

doi:10.18632/oncotarget.3697

Abstract

Castration-resistant prostate cancer (CRPC) remains the most critical challenge in the clinical management of prostate cancer (PCa). Reactive stromal changes in PCa are likely involved in the emergence of CRPC. In the present study, we identified a novel oncogene termed COL6A1 which was upregulated in the reactive stroma of CRPC. We established an androgen-independent LNCaP (LNCaP-AI) cell line in steroid-reduced (SR) medium within 2 months. We examined COL6A1 expression with western blot during the LNCaP-AI induction, and studied the function of COL6A1 in vitro and in vivo. Immunohistochemical staining of COL6A1 was performed in ten pairs of androgen-sensitive PCa and CRPC samples. We demonstrated that COL6A1 expression was markedly increased in LNCaP-AI cells and CRPC tissues compared with LNCaP cells and paired androgen-sensitive PCa specimens. In vitro, COL6A1 knockdown resulted in G1-S cell cycle arrest and descended vitality. Overexpression of COL6A1 was associated with accelerated S phase entry and elevated vitality in prostate cancer cells. COL6A1 also promoted tumorigenesis of LNCaP cells in vivo. Taken together, these data suggest an important role of COL6A1 in the molecular etiology of castration-resistant prostate cancer, and support the potential use of COL6A1 in CRPC therapy.

Highlights

Androgen-deprivation therapy (ADT) is typically employed as the first-line treatment for locally advanced or metastatic prostate cancer (PCa)
COL6A1 expression was upregulated stepwise under SR conditions (Figure 1B).We www.impactjournals.com/oncotarget analyzed the IHC scores of COL6A1 in androgendependent prostate cancer (ADPC) and castration-resistant prostate cancer (CRPC) specimens (Figure 1C)
COL6A1 was upregulated in CRPC specimens.The tumor stroma was enriched in many CPRC specimens

Summary

Introduction

Androgen-deprivation therapy (ADT) is typically employed as the first-line treatment for locally advanced or metastatic prostate cancer (PCa). Considerable recent efforts toward elucidating the molecular mechanisms of castration-resistant prostate cancer (CRPC) suggest that stromal-epithelial interactions play a key role in response to castration therapy [1]. The tumor-associated stroma within the cancer is called reactive stroma. Trichrome stain makes it easy to distinguish normal stroma from reactive stroma. Previous studies reported that reactive stroma was associated with advanced tumor stage in PCa [3] and could be used as a predictor of reduced recurrence-free survival [4, 5]. Further studies suggested that the reactive stroma surrounding prostate tumor lesions performed critical roles, including supporting tumor cell proliferation and inducing tumorigenesis and metastasis [2]

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Results

Conclusion