Expression of Concern: miR‐145 sensitizes ovarian cancer cells to paclitaxel by targeting Sp1 and Cdk6

Abstract

Multidrug resistance (MDR) remains a major obstacle to effective chemotherapy treatment in ovarian cancer. In our study, paclitaxel-resistant ovarian cancer patients and cell lines had decreased miR-145 levels and expressed high levels of Sp1 and Cdk6. Introducing miR-145 into SKOV3/PTX and A2780/PTX cells led to a reduction in Cdk6 and Sp1 along with downregulation of P-gp and pRb. These changes resulted in increased accumulation of antineoplastic drugs and G1 cell cycle arrest, which rendered the cells more sensitive to paclitaxel in vitro and in vivo. These effects could be reversed by reintroducing Sp1 or Cdk6 into cells expressing high levels of miR-145, resulting in restoration of P-gp and pRb levels. Furthermore, we confirmed that both Cdk6 and Sp1 are targets of miR-145. Intriguingly, demethylation with 5-aza-dC led to reactivation of miR-145 expression in drug-resistant ovarian cancer cell lines, which also resulted in increased sensitivity to paclitaxel. Collectively, these findings begin to elucidate the role of miR-145 as an important regulator of chemoresistance in ovarian cancer by controlling both Cdk6 and Sp1.Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Because of the absence of early symptoms, most patients are diagnosed at an advanced stage. Chemotherapy is one of the most frequently used treatment modalities for advanced-stage ovarian cancer patients. Although initial responsiveness to first-line chemotherapy consisting of a platinum-containing compound in combination with paclitaxel (PTX) is high, up to 80% of patients eventually relapse and become platinum/taxane resistant. Therefore, a better understanding of the mechanisms involved in MDR ovarian cancer and more effective therapeutic approaches are immediately required.1 Multiple mechanisms that mediate intrinsic or acquired resistance to paclitaxel have been identified. A major contributor to resistance is the active export of drugs by transmembrane polysubstrate efflux pumps that prevent drugs from reaching their intracellular targets, and a highly studied member of this family is multidrug resistance-1 (MDR1). MDR1 encodes for the membrane transporter P-glycoprotein (P-gp), whose substrates included a wide array of toxins and commonly used chemotherapeutic agents, including taxanes and anthracyclines. 2 Cell cycle dysregulation is another common molecular finding in ovarian cancer, and the cyclin-dependent kinases (Cdks) represent attractive targets in this pathway. For example, inhibition of Cdk6, one of the powerful cell cycle progression regulators, showed encouraging effects in animal experiments and clinical trials. MicroRNAs (miRNAs) are small, noncoding RNA molecules that negatively regulate a large number of proteinencoding genes via either mRNA degradation or translational silencing. Evidence is emerging for roles of miRNAs in modulating drug sensitivity/resistance of cells, 4,5 specifically for one class of miRNAs that target survival pathways or pathways that regulate apoptosis sensitivity, such ...

The expression of CDK1 is associated with proliferation and can be a prognostic factor in epithelial ovarian cancer

“…In ovarian tumors, it is also shown that some cyclindependent kinases (CDK2, CDK4, CDK6, CDK12) were closely related to the survival and therapy for ovarian cancer patients [13][14][15][16]. Moreover, in several human cancers, the role of CDK1 has been well characterized.…”

The Network of Non-coding RNAs in Cancer Drug Resistance

“…miR-145 targeting of MDR1 helps to restore drug efficacy in resistant cells and in vivo models of bladder cancer and BC (200, 201). Moreover miR-145 confirmed its role in reducing chemoresistance also with paclitaxel (202) and doxorubicin (203), possibly via regulation of EMT.…”

“…Paclitaxel is used to treat a number of solid cancers that include lung, ovarian, breast and pancreatic tumors (308). A number of studies produced evidence that loss of non-coding RNAs regulation can modify chemoresistance to taxol (202, 309–313). miR-182 is often up-regulated in cancers; it can enhance cell proliferation, invasion and it plays an important role in drug resistance.…”

MicroRNA-149 targets specificity protein 1 to suppress human tongue squamous cell carcinoma cell proliferation and motility

“…miR-145, miR-133a, miR-133b, miR-22 and miR-335 serve an important role in the biology of gastric cancer by regulating SP1 directly (41)(42)(43). miR-145 was also found to regulate SP1 in ovarian cancer cells sensitized to paclitaxel (44). In esophageal carcinoma, Wang et al (45) found that ectopic miR-429 suppressed cell invasion and induced cell apoptosis via the blockade of SP1.…”