miR‐126 reduces trastuzumab resistance by targeting PIK3R2 and regulating AKT/mTOR pathway in breast cancer cells

Abstract

MicroRNAs (miRNAs) have been found to play a key role in drug resistance. In the current study, we aimed to explore the potential role of miR‐126 in trastuzumab resistance in breast cancer cells. We found that the trastuzumab‐resistant cell lines SKBR3/TR and BT474/TR had low expression of miR‐126 and increased ability to migrate and invade. The resistance, invasion and mobilization abilities of the cells resistant to trastuzumab were reduced by ectopic expression of miR‐126 mimics. In comparison, inhibition of miR‐126 in SKBR3 parental cells had the opposite effect of an increased resistance to trastuzumab as well as invasion and migration. It was also found that miR‐126 directly targets PIK3R2 in breast cancer cells. PIK3R2‐knockdown cells showed decreased resistance to trastuzumab, while overexpression of PIK3R2 increased trastuzumab resistance. In addition, our finding showed that overexpression of miR‐126 reduced resistance to trastuzumab in the trastuzumab‐resistant cells and that inhibition of the PIK3R2/PI3K/AKT/mTOR signalling pathway was involved in this effect. SKBR3/TR cells also showed increased sensitivity to trastuzumab mediated by miR‐126 in vivo. In conclusion, the above findings demonstrated that overexpression of miR‐126 or down‐regulation of its target gene may be a potential approach to overcome trastuzumab resistance in breast cancer cells.

Potential Role of miRNAs in the Acquisition of Chemoresistance in Neuroblastoma

“…Down-regulated in MYCN-amplified NB [22,29] and in chemoresistant NB [13] Down-regulated in cervical [30], breast [31,32] gastric [32,33], and lung [34] cancer, osteosarcoma [35], and mesothelioma [36] miR-19b 7.75 Up-regulated in chemoresistant NB [37] Down-regulated in breast [38] and colon [39] cancer and leukemia [40] miR-26b 47.87 Not evaluated Down-regulated in chemoresistant colorectal [41], gastric [42], laryngeal [43], and hepatocellular carcinoma [44,45] cancer and in glioma [46] [48], breast [49], and gastric cancer [50] miR-29c 9.27 Not evaluated Down-regulated in ovarian [51], endometrial [52], gastric [53], and small cell lung [54] cancer, glioma [55,56], and leukemia [57,58] miR-34c 7.49 Not evaluated Down-regulated in colon [59], gastric [60,61], and ovarian [62,63] cancer, and osteosarcoma [64] miR-126a 9.66 Not evaluated Down-regulated in colorectal [65] and breast cancer [66] and in renal cell carcinoma [67] miR-218 12.30…”

“…In detail, miR-27b and miR-16-1 expression levels were found to be reduced by 33.1 and 23.5 fold, respectively, and miR-218 expression was diminished by 9.09 fold, while miR-15a, miR-126, and miR-19b were down-regulated (slightly, but significantly) by 2.8, 2.7, and 1.73 fold, respectively. [59], gastric [60,61], and ovarian [62,63] cancer, and osteosarcoma [64] miR-126a 9.66 Not evaluated Down-regulated in colorectal [65] and breast cancer [66] and in renal cell carcinoma [67] miR-218 12.30 Up-regulated in MYCN-amplified and in metastatic NB [68][69][70] Down-regulated in glioma cells [71], colorectal [72], gallbladder [73], bladder [74], and lung cancer [75,76] miR-338 15.99 Down-regulated in resistant NB [77,78] Down-regulated in esophageal squamous carcinoma cells [79] miR-497 6.92…”

BRD9 inhibition promotes PUMA-dependent apoptosis and augments the effect of imatinib in gastrointestinal stromal tumors

“…Western blotting was performed as described in previous studies [ 35 , 36 ]. Briefly, total protein was extracted with RIPA buffer (Sigma, MO, USA), followed by the addition of protease inhibitors from Bimake (TX, USA) and phosphate inhibitors (Service Bio, Wuhan, China).…”

SD‐36 promotes growth inhibition and induces apoptosis via suppression of Mcl‐1 in glioma

“…Real‐time PCR was performed following previous studies 21,22 . Total cellular RNA was isolated using TRIzol reagent from Sigma Chemical according to the provided instructions and reverse‐transcribed using the reverse transcriptase SuperScript III from Promega (Madison, WI).…”