title: MUC13 overexpression in renal cell carcinoma plays a central role in tumor progression and drug resistance.
abstract: Metastatic renal cell carcinoma is a largely incurable disease, and existing treatments targeting angiogenesis and tyrosine kinase receptors are only partially effective. Here we reveal that MUC13, a cell surface mucin glycoprotein, is aberrantly expressed by most renal cell carcinomas, with increasing expression positively correlating with tumor grade. Importantly, we demonstrated that high MUC13 expression was a statistically significant independent predictor of poor survival in two independent cohorts, particularly in stage 1 cancers. In cultured renal cell carcinoma cells MUC13 promoted proliferation and induced the cell cycle regulator, cyclin D1, and inhibited apoptosis by inducing the anti-apoptotic proteins, BCL-xL and survivin. Silencing of MUC13 expression inhibited migration and invasion, and sensitized renal cancer cells to killing by the multi-kinase inhibitors used clinically, sorafenib and sunitinib, and reversed acquired resistance to these drugs. Furthermore, we demonstrated that MUC13 promotion of renal cancer cell growth and survival is mediated by activation of nuclear factor κB, a transcription factor known to regulate the expression of genes that play key roles in the development and progression of cancer. These results show that MUC13 has potential as a prognostic marker for aggressive early stage renal cell cancer and is a plausible target to sensitize these tumors to therapy.
authors.affiliation: Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Sheng
authors.affiliation: Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.
authors.forename: Choa Ping
authors.initials: CP
authors.lastname: Ng
authors.affiliation: Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.
authors.forename: Rohan
authors.initials: R
authors.lastname: Lourie
authors.affiliation: Ghrelin Research Group, Translational Research Institute-Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia.|Comparative and Endocrine Biology Laboratory, Translational Research Institute-Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia.
authors.forename: Esha T
authors.initials: ET
authors.lastname: Shah
authors.affiliation: Cancer Biology Group, Mater Research Institute-University of Queensland, Brisbane, QLD, Australia.
authors.forename: Yaowu
authors.initials: Y
authors.lastname: He
authors.affiliation: Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.
authors.forename: Kuan Yau
authors.initials: KY
authors.lastname: Wong
authors.affiliation: Ghrelin Research Group, Translational Research Institute-Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia.|Comparative and Endocrine Biology Laboratory, Translational Research Institute-Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia.
authors.forename: Inge
authors.initials: I
authors.lastname: Seim
authors.affiliation: Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.
authors.forename: Iulia
authors.initials: I
authors.lastname: Oancea
authors.affiliation: Centre for Kidney Disease Research, The University of Queensland School of Medicine, Translational Research Institute, Brisbane, QLD, Australia.
authors.forename: Christudas
authors.initials: C
authors.lastname: Morais
authors.affiliation: Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.|Ghrelin Research Group, Translational Research Institute-Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia.|Comparative and Endocrine Biology Laboratory, Translational Research Institute-Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia.
authors.forename: Penny L
authors.initials: PL
authors.lastname: Jeffery
authors.affiliation: Cancer Biology Group, Mater Research Institute-University of Queensland, Brisbane, QLD, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Hooper
authors.affiliation: Centre for Kidney Disease Research, The University of Queensland School of Medicine, Translational Research Institute, Brisbane, QLD, Australia.
authors.forename: Glenda C
authors.initials: GC
authors.lastname: Gobe
authors.affiliation: Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.
authors.forename: Michael A
authors.identifier: 0000-0002-8375-2675
authors.initials: MA
authors.lastname: McGuckin
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007124:Immunoenzyme Techniques; D007211:Indoles / Q000008:administration & dosage; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009077:Mucins / Q000378:metabolism*; D009367:Neoplasm Staging; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage; D011379:Prognosis; D011758:Pyrroles / Q000008:administration & dosage; D000077157:Sorafenib; D000077210:Sunitinib; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D007211:Indoles; C429552:MUC13 protein, human; D009077:Mucins; D010671:Phenylurea Compounds; D011758:Pyrroles; D009536:Niacinamide; D000077157:Sorafenib; D000077210:Sunitinib
keywords: MUC13; NFκB; apoptosis sorafenib; prognostic marker; proliferation; renal cell carcinoma; sunitinib