Abstract
BackgroundEpithelial ovarian cancer (EOC) is the most lethal cancer in female genital tumors. New disease markers and novel therapeutic strategies are urgent to identify considering the current status of treatment. Receptor tyrosine kinases family plays critical roles in embryo development and disease progression. However, ambivalent research conclusions of ROR2 make its role in tumor confused and the underlying mechanism is far from being understood. In this study, we sought to clarify the effects of ROR2 on high-grade serous ovarian carcinoma (HGSOC) cells and reveal the mechanism.MethodsImmunohistochemistry assay and western-blot assay were used to detect proteins expression. ROR2 overexpression adenovirus and Lentivirus were used to create ROR2 overexpression model in vitro and in vivo, respectively. MTT assay, colony formation assay and transwell assay were used to measure the proliferation, invasion and migration ability of cancer cells. Flow cytometry assay was used to detect cell apoptosis rate. Whole transcriptome analysis was used to explore the differentially expressed genes between ROR2 overexpression group and negative control group. SiRNA targeted IRE1α was used to knockdown IRE1α. Kira6 was used to inhibit phosphorylation of IRE1α.ResultsExpression of ROR2 was significantly lower in HGSOC tissues compared to normal fallopian tube epithelium or ovarian surface epithelium tissues. In HGSOC cohort, patients with advanced stages or positive lymph nodes were prone to express lower ROR2. Overexpression of ROR2 could repress the proliferation of HGSOC cells and induce cell apoptosis. RNA sequencing analysis indicated that ROR2 overexpression could induce unfold protein response. The results were also confirmed by upregulation of BIP and phosphorylated IRE1α. Furthermore, pro-death factors like CHOP, phosphorylated JNK and phosphorylated c-Jun were also upregulated. IRE1α knockdown or Kira6 treatment could reverse the apoptosis induced by ROR2 overexpression. Finally, tumor xenograft experiment showed ROR2 overexpression could significantly repress the growth rate and volume of transplanted tumors.ConclusionsTaken together, ROR2 downregulation was associated with HGSOC development and progression. ROR2 overexpression could repress cell proliferation and induce cell apoptosis in HGSOC cells. And the underlying mechanism might be the activation of IRE1α/JNK/CHOP pathway induced by ROR2.
Highlights
Epithelial ovarian cancer (EOC) is the most lethal cancer in female genital tumors due to absence of screening methods and limited treatments to recurrence [1]
ROR2 was downregulated in high-grade serous ovarian carcinoma (HGSOC) tissues and its expression was correlated with International Federation of Gynecology and Obstetrics (FIGO) stages To detect whether ROR2 expression altered in HGSOC development, we analyzed ROR2 protein level in 23 HGSOC patients and 23 normal control tissues
Gene expression data including HGSOC tissues and normal fallopian tube epithelium (FTE) or ovarian surface epithelium (OSE) tissue samples were downloaded from Gene Expression Omnibus (GEO) and mRNA level of ROR2 was analyzed with the “limma” package
Summary
Epithelial ovarian cancer (EOC) is the most lethal cancer in female genital tumors due to absence of screening methods and limited treatments to recurrence [1]. Receptor tyrosine kinases (RTKs) family are found to play critical roles in embryo development and disease progression [3]. Compared with the opinion that ROR2 works as tumor promoter in initial studies, more and more researches show ROR2 plays dual roles in tumors depending on tumor type and tumor context. New disease markers and novel therapeutic strategies are urgent to identify considering the current status of treatment. Receptor tyrosine kinases family plays critical roles in embryo development and disease progression. We sought to clarify the effects of ROR2 on high-grade serous ovarian carcinoma (HGSOC) cells and reveal the mechanism
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