Abstract
Effective treatments for patients with castration‐resistant prostate cancer (CRPC) have not yet been established. Novel approaches for identification of putative therapeutic targets for CRPC are needed. Analyses of RNA sequencing of microRNA (miRNA) expression revealed that miR‐99a‐3p (passenger strand) is significantly downregulated in several types of cancers. Here, we aimed to identify novel miR‐99a‐3p regulatory networks and therapeutic targets for CRPC. Ectopic expression of miR‐99a‐3p significantly inhibited cancer cell proliferation, migration, and invasion in PCa cells. Non‐SMC condensin I complex subunit G (NCAPG) was a direct target of miR‐99a‐3p in PCa cells. Overexpression of NCAPG was detected in CRPC clinical specimens and was significantly associated with shorter disease‐free survival and advanced clinical stage. Knockdown of NCAPG inhibited cancer cell aggressiveness. The passenger strand miR‐99a‐3p acted as an antitumor miRNA in naïve PCa and CRPC. NCAPG was regulated by miR‐99a‐3p, and its overexpression was involved in CRPC pathogenesis. Involvement of passenger strand of miRNA in cancer pathogenesis is novel concept, and identification of antitumor miRNA regulatory networks in CRPC might be provided novel prognostic markers and therapeutic targets for this disease.
Highlights
In developed countries, prostate cancer (PCa) is one of the most commonly diagnosed cancers, identified by prostate-specific antigen (PSA) screening; PCa is the third leading cause of cancer-related death among men [1]
We have sequentially identified the functional significance of passenger strands of miRNAs in cancer cells based on miRNA signatures [11,12,13,14,15]
We focused on miR-99a-5p whose expression was significantly downregulated in our miRNA signature of metastatic castration-resistant prostate cancer (CRPC) [15] and investigated the functional roles including passenger strand miR-99a-3p in naïve PCa and CRPC cells
Summary
Prostate cancer (PCa) is one of the most commonly diagnosed cancers, identified by prostate-specific antigen (PSA) screening; PCa is the third leading cause of cancer-related death among men [1]. During ADT treatment, PCa cells acquire ADT treatment resistance and progress to a lethal pathology known as castration-resistant prostate cancer (CRPC) [2]. Cancer cells that have reached CRPC can cause distant metastasis, and effective treatments for patients with CRPC have not yet been established [3]. MicroRNAs (miRNAs) are endogenous small RNAs (molecules 18–23 bases in length) that act as central players regulating the expression control of protein-coding and protein-noncoding RNAs [4, 5]. A single miRNA can directly regulate a vast number of RNAs in human cells [6]. Aberrant expression of miRNAs can disrupt normal control of RNA expression in cancer cells. Dysregulation of miRNAs is contributed to cancer cell malignancies, such as progression, metastasis, and treatment resistance [7,8,9,10]
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