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Background: Multidrug resistance (MDR) is one of the reasons for treatment failure in oral squamous cancer patients; however, the MDR mechanisms remain elusive.Methods: Two human oral squamous cell carcinoma (OSCC) cell lines, CAL27 and SCC9, were analyzed by stepwise selection upon exposure to 5-fluorouracil (5-FU) and cisplatin (CDDP) for MDR cell line establishment, and cell viability was analyzed by CCK8 assays. Transcriptomes of the CAL27 and CAL27-MDR cells were analyzed by RNA-seq assay. The molecules in Sonic hedgehog (Shh) signal pathway and MDR related pathway were selected for validation by qRT-PCR and Western blot. Human OSCC tissues were applied for immunohistochemical and clinicopathological analysis.Results: The OSCC-MDR cell lines with resistance to 5-FU and CDDP were successfully established. Protein expression levels of ATP-binding cassette (ABC) transporter ABCC1 and ABCG2 were increased 1.6-fold and 2.1-flod, respectively, in OSCC specimen from the patients with chemotherapy. The RNA-seq assay speculated the activation of Hedgehog (Hh) signaling with the upregulation of SHH, PTCH1, and SMO in OSCC-MDR cells as compared with OSCC cells. Furthermore, immunohistochemical studies confirmed that the high expression of SHH, PTCH1, and SMO in OSCC patients was significantly associated with chemotherapy. Overexpression of SHH increased the chemoresistance in OSCC cells, while the mRNA expression levels of PTCH1 and ABCG2 were increased in OSCC cells upon stimulation with recombinant SHH protein.Conclusions: These results revealed that the activation of Hh signaling pathway regulating ABC transporters is associated MDR in OSCC. [ABSTRACT FROM AUTHOR]