miR-1266 Contributes to Pancreatic Cancer Progression and Chemoresistance by the STAT3 and NF-κB Signaling Pathways

Abstract

Pancreatic cancer is characterized by chemoresistance after several cycles of chemotherapy, which is a major issue responsible for treatment failure of pancreatic cancer. Therefore, it is necessary to explore the specific mechanism underlying chemotherapeutic resistance to overcome this issue. Here we report that miR-1266 is dramatically elevated and correlates with poor survival and chemotherapy response in pancreatic cancer patients. Upregulation of miR-1266 enhanced the chemoresistance of pancreatic cancer cells to gemcitabine (GEM) in vitro and in vivo; conversely, inhibition of miR-1266 yielded the opposite effect. Importantly, silencing of miR-1266 restored the sensitivity of pancreatic cancer cells to GEM in a dose-dependent manner in vivo. Furthermore, our results demonstrate that miR-1266 promotes resistance of pancreatic cancer cells to GEM by targeting multiple negative regulators of the STAT3 and NF-κB pathways, including SOCS3, PTPN11, ITCH, and TNIP1, leading to constitutive activation of STAT3 and NF-κB signaling. Thus, our findings clarify a novel mechanism by which miR-1266 induces chemotherapeutic resistance in pancreatic cancer, indicating that miR-1266 may be used as chemotherapeutic response indicator. Antagomir-1266 as a chemotherapeutic sensitizer, in combination with GEM, may serve as a rational regimen in the treatment of chemotherapy-resistant pancreatic cancer.

Emerging roles for the IL-6 family of cytokines in pancreatic cancer

“…In line with these observations, pancreas-specific deletion of STAT3 in PDAC mouse models revealed reduced inflammation, tumour initiation, progression, and invasive potential [126,172,244], exhibited by significant reduction in ADM, and loss of PanIN-2 and PanIN-3 lesions [172,244]. Moreover, activation of JAK2 and STAT3 has been shown to drive chemotherapy resistance in mouse models [234,245]. Thus, the downstream activation of the JAK/STAT3 signalling axis is thought to be a major contributing factor driving PDAC pathogenesis, and has been proposed as an attractive therapeutic target [246,247].…”

LINC00173.v1 promotes angiogenesis and progression of lung squamous cell carcinoma by sponging miR-511-5p to regulate VEGFA expression

“…The ISH and scoring LINC00173.v1 expression were performed as previously described [18]. Briefly, the slides of frozen section were digested with proteinase K (20 μg/ml, Sangon Biotech, China) for 10 min at 37°C, fixed in 4% paraformaldehyde for 10 min at room temperature, and then dehydrated by immersion in an ethanol gradient and air dried, slides were pre-hybridized by Hybridization Denatured Buffer (Exon Biotechnology, China) at 77°C for 30 min.…”

“…Long noncoding RNAs (lncRNAs) are a class of nonprotein coding RNAs with lengths of more than 200 nucleotides that are implicated in multiple biological processes, including as scaffold proteins between proteins and genes, decoys to bind proteins and enhancers to modulate the transcription of their target genes [15]. Furthermore, the function of lncRNAs as competing endogenous RNAs (ceRNAs) has received great attention as a "miRNA sponge" to disrupt miRNA-mediated degradation of target mRNAs [16], and dysregulation of miRNAs has been extensively demonstrated to contribute to tumorigenesis, progression and metastasis in numerous cancer types [17][18][19], including lung cancer [20,21]. Importantly, several lines of evidence have shown that the lncRNAs mediate in tumor progression by participating in the regulation of VEGF in lung cancer [22].…”

Identification of modules and novel prognostic biomarkers in liver cancer through integrated bioinformatics analysis

“…miR-1266 is identified as a hTERT inhibitor in gastric cancer, which interacts with the 3 0 UTR of hTERT, whereas miR-1266 is significantly reduced in gastric cancer tissues [26]. miR-1266 is significantly elevated in pancreatic cancer, which is associated with poor survival and chemotherapy response in patients with pancreatic cancer [27]. miR-4746 is differentially expressed in several cancers through pan-cancer analysis [28].…”