Kallikrein 4 Is a Proliferative Factor that Is Overexpressed in Prostate Cancer

Klokk, Tove Irene; Kilander, Anette; Xi, Zhijun; Wæhre, Håkon; Risberg, Bjørn; Danielsen, Håvard E.; Saatcioglu, Fahri

doi:10.1158/0008-5472.can-06-4728

Cited by 84 publications

(96 citation statements)

References 47 publications

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“…There are several mechanisms that are hypothesised for the dysregulation of KLKs in ovarian cancer. Many reports have shown that many KLK mRNA transcripts are over-expressed in cancer (Klokk et al, 2007;Mange et al, 2008;Pettus et al, 2009). Hormonal control is another postulated mechanism (Yousef and Diamandis, 1999;Shaw and Diamandis, 2008;Lai et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

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Three dysregulated miRNAs control kallikrein 10 expression and cell proliferation in ovarian cancer

et al. 2010

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BACKGROUND: Kallikrein-related peptidases (KLKs) are a family of serine proteases that have been shown to be dysregulated in several malignancies including ovarian cancer. The control of kallikrein genes and their physiological function in cancer is not well understood. We hypothesized that microRNAs (miRNAs) represent a novel mechanism for post-transcriptional control of KLK expression in cancer. METHODS: We first analysed miRNA expression in ovarian cancer in silico. A total of 98 miRNAs were reported to have altered expression in ovarian cancer. Three of these miRNAs were predicted to target KLK10. We experimentally verified the predicted miR -KLK10 interaction using two independent techniques, a luciferase assay with a construct containing the KLK10 3 0 untranslated region (UTR), pMIR -KLK10, and measuring KLK10 protein levels after transfection with miRNA. RESULTS: When we co-transfected cells with pMIR -KLK10 and either let-7f, miR-224, or mR-516a, we saw decreased luciferase signal, suggesting that these miRNAs can target KLK10. We then examined the effect of these three miRNAs on KLK10 protein expression and cell growth. Transfection of all miRNAs, let-7f, miR-224, and miR-516a led to a decrease in protein expression and cellular growth. This effect was shown to be dose dependent. The KLK10 protein levels were partially restored by co-transfecting let-7f and its inhibitor. In addition, there was a slight decrease in KLK10 mRNA expression after transfection with let-7f. CONCLUSIONS: Our results confirm that KLKs can be targeted by more than one miRNA. Increased expression of certain miRNAs in ovarian cancer can lead to decreased KLK protein expression and subsequently have a negative effect on cell proliferation. This dose-dependent effect suggests that a 'tweaking' or 'fine-tuning' mechanism exists in which the expression of one KLK can be controlled by multiple miRNAs. These data together suggest that miRNA may be used as potential therapeutic options and further studies are required.

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Section: Discussionmentioning

confidence: 99%

“…Reports have shown that siRNA and RNAi were able to knockdown kallikrein gene and protein expression (Bando et al, 2006;Klokk et al, 2007;Shinoda et al, 2007). It should be noted, however, that the endogenous or exogenous siRNAs and synthetic RNAi do not function exactly similar to miRNAs (Yousef, 2008).…”

Section: Discussionmentioning

confidence: 99%

Three dysregulated miRNAs control kallikrein 10 expression and cell proliferation in ovarian cancer

et al. 2010

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“…(20) KLK4, a more recently identified member, is also specific to prostate for expression, is androgen regulated and is overexpressed in prostate cancer compared to normal prostate. (19) Recent studies have revealed that KLK4 has potential roles in prostate cancer cell proliferation, (21) epithelial-mesenchyme transition, (22) extracellular matrix protein degradation (23) and the mediation of cellular interactions with osteoblasts in bone metastases, (24) all essential aspects of prostate carcinogenesis. KLK4 might therefore have potential as a therapeutic target in prostate cancer therapy.…”

Section: Kallikreinsmentioning

confidence: 99%

Androgen signaling and its interactions with other signaling pathways in prostate cancer

2007

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SummaryProstate cancer is the most frequently diagnosed nonskin cancer and the third leading cause of cancer mortality in men. In the initial stages, prostate cancer is dependent on androgens for growth, which is the basis for androgen ablation therapy. However, in most cases, prostate cancer progresses to a hormone refractory phenotype for which there is no effective therapy available at present. The androgen receptor (AR) is required for prostate cancer growth in all stages, including the relapsed, ''androgen-independent'' tumors in the presence of very low levels of androgens. This review focuses on AR function and AR-target genes and summarizes the major signaling pathways implicated in prostate cancer progression, their crosstalk with each other and with AR signaling. This complex network of interactions is providing a deeper insight into prostate carcinogenesis and may form the basis for novel diagnostic and therapeutic strategies. IntroductionProstate adenocarcinoma is the most frequently diagnosed non-cutaneous male malignancy and the third leading cause of cancer-related death in men in most western industrialized countries. (1) It is estimated that around 660,000 men worldwide will be diagnosed with prostate cancer and 250,000 men will die from it in 2010; thus, it will remain a major health problem in the future. (1) It was more than 60 years ago that the important role of male sex hormones (androgens) for the development and growth of prostate cancer was demonstrated. (2) Accordingly, androgen ablation therapy has been the main line of therapy for prostate cancer. Therefore, much of the focus in prostate cancer research to date has naturally been on androgens, how to decrease the androgens in the circulation and how to inhibit the androgen receptor (AR).In addition to AR signaling, it has now become evident that other signaling pathways, as well as non-genomic and genomic alterations, are involved in prostate cancer development and progression. Furthermore, recent studies indicated that signaling through AR has a critical role even after androgen ablation and disease progression (for review see Ref.3). In the following sections, we give an overview of androgen signaling in prostate cancer, with a special focus on recent findings about AR function and AR target genes. We then review the involvement of other central signaling pathways in prostate cancer, with a special focus on their cross-talk with the AR signaling pathway. Clinical implications of these findings and potential directions for future research are also outlined.

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“…Unlike luminal cells, however, and in common with basal cells, cancer cells maintain the ability to proliferate. Although a defining feature of prostate cancer is the complete loss of the basal cell layer, there is evidence for a maintained expression of genes normally restricted to basal cells, including MET (Pisters et al, 1995), BCL-2 (McDonnell et al, 1992), SOX9 (Wang et al, 2007), KLK4 (Klokk et al, 2007) and S100A9 (Hermani et al, 2005). Furthermore, the cancer-initiating cell is widely believed to be of basal origin (Bui and Reiter, 1998), expressing known basal markers including keratin (K)14, a2b1 integrin and CD44 (Collins et al, 2005;Patrawala et al, 2007).…”

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confidence: 99%

TEAD1 and c-Cbl are novel prostate basal cell markers that correlate with poor clinical outcome in prostate cancer

et al. 2008

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Prostate cancer is the most frequently diagnosed male cancer, and its clinical outcome is difficult to predict. The disease may involve the inappropriate expression of genes that normally control the proliferation of epithelial cells in the basal layer and their differentiation into luminal cells. Our aim was to identify novel basal cell markers and assess their prognostic and functional significance in prostate cancer. RNA from basal and luminal cells isolated from benign tissue by immunoguided laser-capture microdissection was subjected to expression profiling. We identified 112 and 267 genes defining basal and luminal populations, respectively. The transcription factor TEAD1 and the ubiquitin ligase c-Cbl were identified as novel basal cell markers. Knockdown of either marker using siRNA in prostate cell lines led to decreased cell growth in PC3 and disrupted acinar formation in a 3D culture system of RWPE1. Analyses of prostate cancer tissue microarray staining established that increased protein levels of either marker were associated with decreased patient survival independent of other clinicopathological metrics. These data are consistent with basal features impacting on the development and clinical course of prostate cancers.

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Kallikrein 4 Is a Proliferative Factor that Is Overexpressed in Prostate Cancer

Abstract: Kallikrein 4 (

Cited by 84 publications

References 47 publications

Three dysregulated miRNAs control kallikrein 10 expression and cell proliferation in ovarian cancer

Three dysregulated miRNAs control kallikrein 10 expression and cell proliferation in ovarian cancer

Androgen signaling and its interactions with other signaling pathways in prostate cancer

TEAD1 and c-Cbl are novel prostate basal cell markers that correlate with poor clinical outcome in prostate cancer

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