Keratin 5 overexpression is associated with serous ovarian cancer recurrence and chemotherapy resistance

Carmela Ricciardelli,Peter Hoffmann,Noor A Lokman,Martin K Oehler,Andrew Ruszkiewicz,Miranda P Ween,Carmen E Pyragius,Anne M Macpherson

doi:10.18632/oncotarget.14867

Carmela Ricciardelli, Peter Hoffmann + Show 6 more

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https://doi.org/10.18632/oncotarget.14867

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Abstract

This study investigated the clinical significance of keratin 5 and 6 expression in serous ovarian cancer progression and chemotherapy resistance. KRT5 and KRT6 (KRT6A, KRT6B & KRT6C) gene expression was assessed in publically available serous ovarian cancer data sets, ovarian cancer cell lines and primary serous ovarian cancer cells. Monoclonal antibodies which detect both K5/6 or only K5 were used to assess protein expression in ovarian cancer cell lines and a cohort of high grade serous ovarian carcinomas at surgery (n = 117) and after neoadjuvant chemotherapy (n = 21). Survival analyses showed that high KRT5 mRNA in stage III/IV serous ovarian cancers was significantly associated with reduced progression-free (HR 1.38, P < 0.0001) and overall survival (HR 1.28, P = 0.013) whilst high KRT6 mRNA was only associated with reduced progression-free survival (HR 1.2, P = 0.031). Both high K5/6 (≥ 10%, HR 1.78 95% CI; 1.03−2.65, P = 0.017) and high K5 (≥ 10%, HR 1.90, 95% CI; 1.12−3.19, P = 0.017) were associated with an increased risk of disease recurrence. KRT5 but not KRT6C mRNA expression was increased in chemotherapy resistant primary serous ovarian cancer cells compared to chemotherapy sensitive cells. The proportion of serous ovarian carcinomas with high K5/6 or high K5 immunostaining was significantly increased following neoadjuvant chemotherapy. K5 can be used to predict serous ovarian cancer prognosis and identify cancer cells that are resistant to chemotherapy. Developing strategies to target K5 may therefore improve serous ovarian cancer survival.

Highlights

Ovarian cancer is the most lethal gynaecological cancer and the sixth most common cause of cancer related death among Western women [1]
Survival analyses showed that high KRT5 mRNA in stage III/IV serous ovarian cancers was significantly associated with reduced progression-free (HR 1.38, P < 0.0001) and overall survival (HR 1.28, P = 0.013) whilst high KRT6 mRNA was only associated with reduced progression-free survival (HR 1.2, P = 0.031)
K5 can be used to predict serous ovarian cancer prognosis and identify cancer cells that are resistant to chemotherapy

Summary

Introduction

Ovarian cancer is the most lethal gynaecological cancer and the sixth most common cause of cancer related death among Western women [1]. Ovarian cancers represent only 30% of cancers of the female genital tract, they are responsible for half of the deaths [1]. A greater understanding of the mechanisms involved in the progression of ovarian cancer will aid in the discovery of novel molecular prognostic indicators as well as new therapeutic targets. To increase our understanding of the molecular mechanisms involved in ovarian cancer progression and to identify novel therapeutic targets we recently studied the interaction of ovarian cancer and peritoneal cells [3,4,5]. Keratins K5 and K6c were amongst the proteins that were identified in the ovarian cancer peritoneal cell co-culture secretome by MALDI-TOF/TOF mass spectrometry [5]

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