Lin28 Mediates Paclitaxel Resistance by Modulating p21, Rb and Let-7a miRNA in Breast Cancer Cells

Abstract

Resistance to chemotherapy is a major obstacle for the effective treatment of cancers. Lin28 has been shown to contribute to tumor relapse after chemotherapy; however, the relationship between Lin28 and chemoresistance remained unknown. In this study, we investigated the association of Lin28 with paclitaxel resistance and identified the underlying mechanisms of action of Lin28 in human breast cancer cell lines and tumor tissues. We found that the expression level of Lin28 was closely associated with the resistance to paclitaxel treatment. The T47D cancer cell line, which highly expresses Lin28, is more resistant to paclitaxel than the MCF7, Bcap-37 or SK-BR-3 cancer cell lines, which had low-level expression of Lin28. Knocking down of Lin28 in Lin28 high expression T47D cells increased the sensitivity to paclitaxel treatment, while stable expression of Lin28 in breast cancer cells effectively attenuated the sensitivity to paclitaxel treatment, resulting in a significant increase of IC50 values of paclitaxel. Transfection with Lin28 also significantly inhibited paclitaxel-induced apoptosis. We also found that Lin28 expression was dramatically increased in tumor tissues after neoadjuvant chemotherapy or in local relapse or metastatic breast cancer tissues. Moreover, further studies showed that p21, Rb and Let-7 miRNA were the molecular targets of Lin28. Overexpression of Lin28 in breast cancer cells considerably induced p21 and Rb expression and inhibited Let-7 miRNA levels. Our results indicate that Lin28 expression might be one mechanism underlying paclitaxel resistance in breast cancer, and Lin28 could be a potential target for overcoming paclitaxel resistance in breast cancer.

The LIN28/let-7 Pathway in Cancer

“…Accordingly, therapeutics such as shRNAs, siRNAs, and chemical compounds that downregulate LIN28A or LIN28B expression or functional activity are unlikely to have harmful side effects in patients. As mentioned earlier, there is already evidence that downregulation of LIN28A in chemotherapy and radiation-resistant breast cancer cells enhanced their sensitivity to the treatments (Lv et al, 2012; Wang et al, 2013). Suppression of LIN28A by shRNA in human glioblastoma cells caused cell cycle arrest in the G1 phase, enhanced apoptosis, and delayed cell proliferation (Qin et al, 2014).…”

“…However, many patients develop metastasis and/or tumor relapse after 6–10 months (Seo et al, 2007). Lin28 was found to mediate resistance of breast cancer cells to paclitaxel by modulating p21, Rb, and Let-7a miRNAs (Lv et al, 2012). As compared to cells expressing a low level of LIN28A, T47D cancer cells with high expression of Lin28 was shown to be more resistant to paclitaxel.…”

Significant association of combination of OCT4, NANOG, and SOX2 gene polymorphisms in susceptibility and response to treatment in North Indian breast cancer patients

“…Overexpression of LIN28 is known to promote cancer cell proliferation by inhibiting the biogenesis of microRNA let-7 [37,60]. Furthermore, LIN28 overexpression was shown to be correlated with poor prognosis in patients with primary breast tumors [17,32]. Decreased let-7 expression has been linked to increased tumorigenicity and poor patient prognosis in breast as well as many other cancers [12,20,40,59].…”

LIN28A Modulates Splicing and Gene Expression Programs in Breast Cancer Cells

“…LIN28 is expressed in breast cancer tumors, and recent studies have shown that LIN28 is a powerful predictor of poor prognoses and patient clinical outcomes (8,28,29). With this in mind, we were interested in identifying novel LIN28 mRNA targets that could provide insights into the function of LIN28 in breast cancer.…”