Abstract
The acquisition of cancer stem-like properties is believed to be responsible for cancer metastasis and therapeutic resistance in cervical cancer (CC). CC tissues display a high expression level of hexokinase 2 (HK2), which is critical for the proliferation and migration of CC cells. However, little is known about the functional role of HK2 in the maintenance of cancer stem cell-like ability and cisplatin resistance of CC cells. Here, we showed that the expression of HK2 is significantly elevated in CC tissues, and high HK2 expression correlates with poor prognosis. HK2 overexpression (or knockdown) can promote (or inhibit) the sphere-forming ability and cisplatin resistance in CC cells. In addition, HK2-overexpressing CC cells show enhanced expression of cancer stem cell-associated genes (including SOX2 and OCT4) and drug resistance-related gene MDR1. The expression of HK2 is mediated by miR-145, miR-148a, and miR-497 in CC cells. Overexpression of miR-148a is sufficient to reduce sphere formation and cisplatin resistance in CC cells. Our results elucidate a novel mechanism through which miR-148a regulates CC stem cell-like properties and chemoresistance by interfering with the oncogene HK2, providing the first evidence that dysregulation of the miR-148a/HK2 signaling plays a critical role in the maintenance of sphere formation and cisplatin resistance of CC cells. Our findings may guide future studies on therapeutic strategies that reverse cisplatin resistance by targeting this pathway.
Highlights
Cervical cancer (CC) is ranked the fourth most commonly diagnosed cancer in women and is the second-leading cause of cancer-related death among women in developing countries [1]
We explored the expression of hexokinase 2 (HK2) in TCGA CC patients using the UALCAN database
We evaluated the prognostic significance of HK2 in CC patients using the KM plotter database
Summary
Cervical cancer (CC) is ranked the fourth most commonly diagnosed cancer in women and is the second-leading cause of cancer-related death among women in developing countries [1]. The majority of CC patients have an initial response to chemotherapy, such as cisplatin (CDDP), a substantial proportion of patients eventually develop chemoresistance and relapse [2]. A better understanding of the mechanisms underlying CDDP resistance is required to retrieve the chemosensitivity in CC patients. The cancer stem cell theory explains numerous clinical observations, such as the recurrence of tumors after initially successful chemotherapy and/or radiation therapy, and metastasis [3]. Cancer stem cells have been found in many cancer types, including CC [4]. In CC, cancer stem cells have been associated with resistance to commonly used anti-cancer drugs such as CDDP [4]. The molecular mechanisms underlying the induction and maintenance of cancer stem cells in CC remain to be explored
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