Cancer stem cells (CSC) play a central role in cancer metastasis and development of drug resistance. miRNA are important in regulating CSC properties and are considered potential therapeutic targets. Here we report that miR-328–3p (miR-328) is significantly upregulated in ovarian CSC. High expression of miR-328 maintained CSC properties by directly targeting DNA damage binding protein 2, which has been shown previously to inhibit ovarian CSC. Reduced activity of ERK signaling in ovarian CSC, mainly due to a low level of reactive oxygen species, contributed to the enhanced expression of miR-328 and maintenance of CSC. Inhibition of miR-328 in mouse orthotopic ovarian xenografts impeded tumor growth and prevented tumor metastasis. In summary, our findings provide a novel mechanism underlying maintenance of the CSC population in ovarian cancer and suggest that targeted inhibition of miR-328 could be exploited for the eradication of CSC and aversion of tumor metastasis in ovarian cancer.
Significance:
These findings present inhibition of miR-328 as a novel strategy for efficient elimination of CSC to prevent tumor metastasis and recurrence in patients with epithelial ovarian cancer.
◥Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are approved to treat recurrent ovarian cancer with BRCA1 or BRCA2 mutations, and as maintenance therapy for recurrent platinumsensitive ovarian cancer (BRCA wild-type or mutated) after treatment with platinum. However, the acquired resistance against PARPi remains a clinical hurdle. Here, we demonstrated that PARP inhibitor (olaparib)-resistant epithelial ovarian cancer (EOC) cells exhibited an elevated aldehyde dehydrogenase (ALDH) activity, mainly contributed by increased expression of ALDH1A1 due to olaparib-induced expression of BRD4, a member of bromodomain and extraterminal (BET) family protein. We also revealed that ALDH1A1 enhanced microhomology-mediated end joining (MMEJ) activity in EOC cells with inactivated BRCA2, a key protein that promotes homologous recombination (HR) by using an intrachromosomal MMEJ reporter. Moreover, NCT-501, an ALDH1A1-selective inhibitor, can synergize with olaparib in killing EOC cells carrying BRCA2 mutation in both in vitro cell culture and the in vivo xenograft animal model. Given that MMEJ activity has been reported to be responsible for PARPi resistance in HR-deficient cells, we conclude that ALDH1A1 contributes to the resistance to PARP inhibitors via enhancing MMEJ in BRCA2 À/À ovarian cancer cells. Our findings provide a novel mechanism underlying PARPi resistance in BRCA2-mutated EOC cells and suggest that inhibition of ALDH1A1 could be exploited for preventing and overcoming PARPi resistance in EOC patients carrying BRCA2 mutation.
Menisci form between two solid surfaces with the presence of an ultra-thin liquid film. Meniscus and viscous forces contribute to an adhesive force when two surfaces are separated. The adhesive force can be very large and can result in high friction, stiction and possibly high wear. The situation may become more pronounced when the contacting surfaces are ultra-smooth and the normal load is small, as is common for micro-/nanodevices. In this study, equations for meniscus and viscous forces during separation of two flat surfaces, and a sphere and a flat surface, are developed, and the corresponding adhesive forces contributed by these two types of forces are examined. The geometric meniscus curvatures and break point are theoretically determined, and the role of meniscus and viscous forces is evaluated during separation. The influence of separation distance, liquid thickness, meniscus area, separation time, liquid properties and contact angles are analyzed. Critical meniscus areas at which transition in the dominance of meniscus to viscous forces occurs for different given conditions, i.e. various initial liquid thicknesses, contact angles and designated separation time, are identified. The analysis provides a fundamental understanding of the physics of separation process, and insights into the relationships between meniscus and viscous forces. It is also valuable for the design of the interface for various devices.
Adhesive or repulsive forces contributed by both meniscus and viscous forces can be significant and become one of the main reliability issues when the contacting surfaces are ultra smooth, and the normal load is small, as is common for micro/nano devices. In this study, both meniscus and viscous forces during separation for smooth and rough hydrophilic and hydrophobic surfaces are studied. The effects of separation distance, initial meniscus height, separation time, contact angle and roughness are presented. Meniscus force decreases with an increase of separation distance, whereas the viscous force has an opposite trend. Both forces decrease with an increase of initial meniscus height. An increase of separation time, initial meniscus height or a decrease of contact angle leads to an increase of critical meniscus area at which both forces are equivalent. An increase in contact angle leads to a decrease of attractive meniscus force but an increase of repulsive meniscus force (attractive or repulsive dependent on hydrophilic or hydrophobic surface, respectively). Contact angle has a limited effect on the viscous force. For asymmetric contact angles, the magnitude of the meniscus force and the critical meniscus area are in between the values for the two angles. An increase in the number of surface asperities (roughness) leads to an increase of meniscus force; however, its effect on viscous force is trivial. A slightly attractive force is observed for the hydrophobic surface during the end stage of separation though the magnitude is small. The study provides a fundamental understanding of the physics of the separation process and it can be useful for control of the forces in nanotechnology applications.
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