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Specific-detection of clinical samples, systematic functional investigations, and transcriptome analysis reveals that splice variant MUC4/Y contributes to the malignant progression of pancreatic cancer by triggering malignancy- related positive feedback l



Published on:2016-11-28   Views:216

Abstract

BACKGROUND:MUC4 plays important roles in the malignantprogression of human pancreatic cancer. But the huge length of MUC4 genefragment restricts its functional and mechanism research. As one of its splicevariants, MUC4/Y with coding sequence is most similar to that of thefull-length MUC4 (FL-MUC4), together with alternative splicing of the MUC4transcript has been observed in pancreatic carcinomas but not in normalpancreas. So we speculated that MUC4/Y might be involved in malignantprogression similarly to FL-MUC4, and as a research model of MUC4 in pancreaticcancer. The conjecture was confirmed in the present study.

METHODS:MUC4/Y expression was detected by real-timequantitative reverse transcription polymerase chain reaction (qRT-PCR) usinggene-specific probe in the clinic samples. The effects of MUC4/Y were observedby serial in vitro and in vivo experiments based on stable over-expressed cellmodel. The underlying mechanisms were investigated by sequence-basedtranscriptome analysis and verified by qRT-PCR, Western blot and enzyme-linkedimmunosorbent assays.

RESULTS:The detection of clinical samples indicates thatMUC4/Y is significantly positive-correlated with tumor invasion and distantmetastases. Based on stable forced-expressed pancreatic cancer PANC-1 cell model,functional studies show that MUC4/Y enhances malignant activity in vitro and invivo, including proliferation under low-nutritional-pressure, resistance toapoptosis, motility, invasiveness, angiogenesis, and distant metastasis.Mechanism studies indicate the novel finding that MUC4/Y triggersmalignancy-related positive feedback loops for concomitantly up-regulating theexpression of survival factors to resist adverse microenvironment andincreasing the expression of an array of cytokines and adhesion molecules toaffect the tumor milieu.

CONCLUSIONS:In light of the enormity of the potentialregulatory circuitry in cancer afforded by MUC4 and/or MUC4/Y, repressing MUC4transcription, inhibiting post-transcriptional regulation, includingalternative splicing, or blocking various pathways simultaneously may behelpful for controlling malignant progression. MUC4/Y- expression model isproven to a valuable tool for the further dissection of MUC4-mediated functionsand mechanisms.