The Prognostic Relevance of the Proliferation Markers Ki-67 and Plk1 in Early-Stage Ovarian Cancer Patients With Serous, Low-Grade Carcinoma Based on mRNA and Protein Expression

Rödel, Franz; Zhou, Shengtao; Gyorffy, B.; Raab, Monika; Sanhaji, Mourad; Mandal, Ranadip; Martin, Daniel; Becker, Sven; Strebhardt, Klaus

doi:10.3389/fonc.2020.558932

Cited by 20 publications

(18 citation statements)

References 58 publications

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“…Combined with clinicopathological parameters, miR-1539 overexpression was also associated with elevated Ki-67 expression levels. Ki-67 is a well-accepted marker of tumor cell proliferation; it is detected in almost all proliferative phases of the cell cycle, except for the stationary stage ( 40 ). Several studies have confirmed that high Ki-67 levels are associated with a poor CRC prognosis ( 41 – 43 ), suggesting miR-1539 may also be linked to poor CRC outcomes.…”

Section: Discussionmentioning

confidence: 99%

MiR-1539 and Its Potential Role as a Novel Biomarker for Colorectal Cancer

Cui

Ding

et al. 2021

Front. Oncol.

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PurposeWe investigated microRNA (miR) 1539 as a potential biomarker for predicting the risk and pathobiological behavior of colorectal cancer (CRC).MethodsOur strategy consisted of analyzing 100 serum samples from 51 CRC patients, 49 healthy controls (HCs), and another 56 CRC tissue and matched normal adjacent to tumor (NAT) samples. The relative expression levels of miR-1539 in exosomes, serum and tissues were detected and compared in the different groups, using reverse transcription-polymerase chain reaction (RT-qPCR). The diagnostic value and potential function of miR-1539 were investigated using clinicopathological data combined with bioinformatics analysis.ResultsMiR-1539 expression was significantly up-regulated in exosomes (p = 0.003) and cancer tissue (p < 0.001) from CRC patients. MiR-1539 expression levels in serum varied according to different tumor sites (right-sided vs. left-sided, p = 0.047; left-side CRC vs. HCs, p = 0.031). In terms of diagnostic efficacy, miR-1539 expression in exosomes may help distinguish CRC cases from HCs with a sensitivity of 92.2%, and miR-1539 expression in serum may improve the specificity to 96.6% for left-sided CRC diagnosis. When combined with clinicopathological data, serum miR-1539 levels were positively associated with vascular endothelial growth factor (VEGF) expression (p = 0.028), whilst levels in CRC tissue were positively associated with increased Ki-67 levels (p = 0.035). Poorer pathologic differentiation was potentially related to an increased tendency of miR-1539 expression in CRC tissue (p = 0.071). Based on our bioinformatics analysis, miR-1539 may have a significant mechanistic influence on CRC genesis and progression.ConclusionsCirculating or tissue based miR-1539 may be used as a novel potential biomarker for CRC screening, and a predictor of poor clinicopathological behavior in tumors.

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Section: Discussionmentioning

confidence: 99%

MiR-1539 and Its Potential Role as a Novel Biomarker for Colorectal Cancer

Cui

Ding

et al. 2021

Front. Oncol.

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“…In the mucinous subtype of ovarian carcinoma, downregulation of PLK1 with siRNA as well as pharmacological PKL1 inhibition (Volasertib ® and Onvansertib ® , both highly selective ATP-competitive PLK1 inhibitors) [ 276 ] in a xenograft model interferes with cell proliferation inducing mitotic arrest at G2/M phase leading to endoduplication as well as apoptosis [ 277 ]. The complex diversity of PLK1′s role in ovarian cancer becomes obvious in light of PLK1 serving as predictive marker for better prognosis with regard to the progression-free survival in a stage-dependent manner: PLK1 functions as a positive predictor in early-stage of a low-grade serous subtype but not in late-stage based on mRNA and protein expression [ 144 ]. Transcriptomic analysis of serous ovarian carcinomas reveals PLK-signaling events and PLK-dependent differentially expressed genes to be important in tumorigenesis and cancer progression [ 278 ].…”

Section: Ovarian Cancer and Plksmentioning

confidence: 99%

“…Besides Ki67, PLK1 is a suitable stage-dependent marker. At least in a subtype of serous ovarian cancer this could be demonstrated on the level of mRNA expression [ 144 ]. The introduction of DNA microarray technique for determination of PLK levels in clinical use might be of strategical benefit.…”

Section: Targeting Plks In Ovarian Cancermentioning

confidence: 99%

Modelling the Functions of Polo-Like Kinases in Mice and Their Applications as Cancer Targets with a Special Focus on Ovarian Cancer

Kressin

Fietz

Becker

et al. 2021

Cells

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Polo-like kinases (PLKs) belong to a five-membered family of highly conserved serine/threonine kinases (PLK1-5) that play differentiated and essential roles as key mitotic kinases and cell cycle regulators and with this in proliferation and cellular growth. Besides, evidence is accumulating for complex and vital non-mitotic functions of PLKs. Dysregulation of PLKs is widely associated with tumorigenesis and by this, PLKs have gained increasing significance as attractive targets in cancer with diagnostic, prognostic and therapeutic potential. PLK1 has proved to have strong clinical relevance as it was found to be over-expressed in different cancer types and linked to poor patient prognosis. Targeting the diverse functions of PLKs (tumor suppressor, oncogenic) are currently at the center of numerous investigations in particular with the inhibition of PLK1 and PLK4, respectively in multiple cancer trials. Functions of PLKs and the effects of their inhibition have been extensively studied in cancer cell culture models but information is rare on how these drugs affect benign tissues and organs. As a step further towards clinical application as cancer targets, mouse models therefore play a central role. Modelling PLK function in animal models, e.g., by gene disruption or by treatment with small molecule PLK inhibitors offers promising possibilities to unveil the biological significance of PLKs in cancer maintenance and progression and give important information on PLKs’ applicability as cancer targets. In this review we aim at summarizing the approaches of modelling PLK function in mice so far with a special glimpse on the significance of PLKs in ovarian cancer and of orthotopic cancer models used in this fatal malignancy.

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“…In breast cancer, the lack of reproducibility in Κi-67 labelling index scoring has limited its clinical use [ 10 ] and led to an extensive effort to develop an automated scoring system [ 11 , 12 ] and new standardization tools [ 13 ]. In ovarian cancer, Ki-67 is a useful stratification marker in early but not in advanced disease stage [ 14 ]. Additionally, it was recently suggested that Κi-67 is more of a graded than a binary marker, and its expression levels in cycling cells depends on how long they remained quiescent before entering the cell cycle.…”

Section: Introductionmentioning

confidence: 99%

Challenging, Accurate and Feasible: CAF-1 as a Tumour Proliferation Marker of Diagnostic and Prognostic Value

Sykaras

Pergaris

Theocharis

2021

Cancers

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The discovery of novel biomarkers of diagnostic, prognostic, and therapeutic value is a major challenge of current cancer research. The assessment of tumour cell proliferative capacity is pivotal for grading and clinical decision-making, highlighting the importance of proliferation markers as diagnostic and prognostic tools. Currently, the immunohistochemical analysis of Ki-67 expression levels is routinely used in clinical settings to assess tumour proliferation. Inasmuch as the function of Ki-67 is not fully understood and its evaluation lacks standardization, there is interest in chromatin regulator proteins as alternative proliferation markers of clinical value. Here, we review recent evidence demonstrating that chromatin assembly factor 1 (CAF-1), a histone chaperone selectively expressed in cycling cells, is a proliferation marker of clinical value. CAF-1 expression, when evaluated by immunocytochemistry in breast cancer cytology smears and immunohistochemistry in cancer biopsies from several tissues, strongly correlates with the expression of Ki-67 and other proliferation markers. Notably, CAF-1 expression is upregulated in almost all cancers, and CAF-1 overexpression is significantly associated, in most cancer types, with high histological tumour grade, advanced stage, recurrence, metastasis, and decreased patient survival. These findings suggest that CAF-1 is a robust, reproducible, and feasible proliferation marker of prognostic importance. CAF-1 may represent an attractive alternative or complementary to Ki-67 for cancer stratification and clinical guidance.

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The Prognostic Relevance of the Proliferation Markers Ki-67 and Plk1 in Early-Stage Ovarian Cancer Patients With Serous, Low-Grade Carcinoma Based on mRNA and Protein Expression

Cited by 20 publications

References 58 publications

MiR-1539 and Its Potential Role as a Novel Biomarker for Colorectal Cancer

MiR-1539 and Its Potential Role as a Novel Biomarker for Colorectal Cancer

Modelling the Functions of Polo-Like Kinases in Mice and Their Applications as Cancer Targets with a Special Focus on Ovarian Cancer

Challenging, Accurate and Feasible: CAF-1 as a Tumour Proliferation Marker of Diagnostic and Prognostic Value

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