Abstract
High grade type I endometrial cancers have poor prognosis. Interleukin (IL)11 is elevated in tumours and uterine lavage with increasing tumour grade in women. IL11 regulates cell cycle, invasion and migration and we recently demonstrated that IL11 receptor (R)α inhibition impaired low and moderate grade endometrial tumourigenesis in vivo. In this report, we hypothesized that micro-RNA(miR)-1 regulates IL11 and that IL11 promotes high grade endometrial tumour growth. We aimed to determine whether combination treatment using an anti-human IL11Rα blocking antibody (Ab) and doxorubicin chemotherapeutic impairs high grade tumour growth. MiR-1 was absent in human endometrial tumours versus human benign endometrium (n = 10/group). Transfection with miR-1 mimic restored miR-1 expression, down-regulated IL11 mRNA and impaired cell viability in grade 3-derived AN3CA human endometrial epithelial cancer cells. AN3CA cell proliferation was reduced in response to Ab and doxorubicin combination treatment versus Ab, IgG control, or doxorubicin alone. Subcutaneous xenograft tumours were established in female Balb/c athymic nude mice using AN3CA cells expressing IL11 and IL11Rα. Administration of recombinant human IL11 to mice (n = 4/group) activated IL11 downstream target, signal transducers and activators of transcription (STAT3) and significantly increased tumour growth (p < 0.05), suggesting that IL11 promotes high grade tumour growth. IL11Rα blocking Ab reduced STAT3 phosphorylation and combination treatment with doxorubicin resulted in a significant reduction in tumour growth (p < 0.05) compared to Ab, doxorubicin, or IgG control. Our data suggest that therapeutically targeting IL11Rα in combination with doxorubicin chemotherapy could inhibit high grade type I endometrioid cancer growth.
Highlights
Endometrial cancer is the most common invasive gynaecological malignancy in developed countries, with more than 280,000 new cases occurring on average annually [1]
MiR-1 is absent in human endometrial cancer and cell lines and miR-1 mimic down regulates IL11 in AN3CA cells
We recently demonstrated that IL11Rα inhibition reduces low and moderate G1-derived Ishikawa and G2derived HEC1A endometrial xenograft tumour growth and www.impactjournals.com/oncotarget metastasis in ectopic and orthotopic mouse models [20]
Summary
Endometrial cancer is the most common invasive gynaecological malignancy in developed countries, with more than 280,000 new cases occurring on average annually [1]. Grade 1 cancers are described as well differentiated in terms of their morphology These cancers are usually confined to the uterus and have good prognosis following surgical intervention and radiotherapy. Grade 3 cancer cells are arranged in a haphazard or disorganized way and do not form glands; they are described as poorly differentiated and are highly metastatic [4]. Both grade 2 and 3 endometrial cancers have poorer prognosis, compared to grade 1, with metastatic behavior being most closely linked with clinical outcome and cause of death [3]
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