Abstract
High-grade ovarian cancer (HGOC) is the most lethal gynecological cancer, with high metastasis and recurrence. Cancer stem cells (CSCs) are responsible for its apoptosis resistance, cancer metastasis, and recurrence. Thus, targeting CSCs would be a promising strategy for overcoming chemotherapy resistance and improving patient prognosis in HGOC. Among upregulated oncogenic proteins in HGOC, we found that transcription factor SOX9 showed a strong correlation with stemness-regulating ALDH1A1 and was localized predominantly in the cytoplasm of HGOC with lymph node metastasis. In order to address the role of unusual cytoplasmic SOX9 and to explore its underlying mechanism in HGOC malignancy, a Y2H assay was used to identify a necroptotic cell death-associated cytoplasmic protein, receptor-interacting serine/threonine protein kinase 1 (RIPK1), as a novel SOX9-interacting partner and further mapped their respective interacting domains. The C-terminal region containing the transactivation domain of SOX9 interacted with the death domain of R1PK1. Consistent with its stemness-promoting function, SOX9 knockdown in vitro resulted in changes in cell morphology, cell cycle, stem cell marker expression, cell invasion, and sphere formation. Furthermore, in vivo knockdown completely inhibited tumor growth in mouse xenograft model. We propose that cytoplasmic SOX9-mediated cell death suppression would contribute to cancer stem cell survival in HGOC.
Highlights
High-grade ovarian carcinoma (HGOC) represents the most lethal gynecological malignancy and has the worst prognosis due to its high apoptosis resistance and metastasis [1,2].Apoptosis resistance develops in HGOC and increases the risk of cancer recurrence, resulting in a high mortality rate [3]
In order to examine whether the expression of SOX9 and aldehyde dehydrogenase 1 (ALDH1) proteins is associated with lymph node metastasis in HGOC, we used immunohistochemistry to analyze SOX9 and
Quantitative analysis of immunohistochemical staining showed no significant correlation between lymph node metastasis and the expression of
Summary
Apoptosis resistance develops in HGOC and increases the risk of cancer recurrence, resulting in a high mortality rate [3]. Metastasis and recurrence of HGOC are associated with the spread of cancer stem-like cells (CSCs) from the primary tumor to the peritoneal cavity [4]. These CSCs are exclusively tumorigenic and major drivers of tumor formation, progression, metastasis, and apoptosis resistance to chemotherapy and radiation, eventually resulting in cancer recurrence [5] by escaping programmed cell death in various types of cancers [6,7,8]. Platinum-based anticancer drugs that have been used as a first treatment of HGOC patients failed to eliminate apoptosis-resistant CSCs and resulted in tumor metastasis and recurrence, resulting in poor clinical outcomes [2,9].
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