Lung cancer (LC) is the leading cause of cancer-related mortality. However, the molecular mechanisms associated with the development of metastasis is poorly understood. Understanding the biology of LC metastasis is critical to unveil the molecular mechanisms for designing targeted therapies. We developed two genetically engineered LC mouse models- KrasG12D ;Trp53R172H/+ ;Ad-Cre (KPA) and KrasG12D ; Ad-Cre (KA). Survival analysis showed significantly (P=0.0049) shorter survival in KPA tumor-bearing mice as compared to KA, suggesting the aggressiveness of the model. Our transcriptomic data showed high expression of St6galnac-I in KPA compared to KA tumors. ST6GalNAc-I is an O-glycosyltransferase, which catalyzes the addition of sialic acid (SA) to the initiating GalNAc residues forming sialyl Tn (STn) on glycoproteins, such as mucins. Ectopic expression of species-specific p53 mutants in the syngeneic mouse and human LC cells led to increased cell migration and high expression of ST6GalNAc-I, STn, and MUC5AC. Immunoprecipitation of MUC5AC in the ectopically expressing p53R175H cells exhibited higher affinity towards STn. In addition, ST6GalNAc-I knockout (KO) cells also showed decreased migration, possibly due to reduced glycosylation of MUC5AC as observed by low STn on the glycoprotein. Interestingly, ST6GalNAc-I KO cells injected mice developed less liver metastasis (P=0.01) compared to controls, while co-localization of MUC5AC and STn was observed in the liver metastatic tissues of control mice. Collectively, our findings support the hypothesis that mutant p53R175H mediates ST6GalNAc-I expression, leading to the sialyation of MUC5AC, and thus contribute to LC liver metastasis.
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Lakshmanan, Imayavaramban; Chaudhary, Sanjib; Vengoji, Raghupathy; Seshacharyulu, Parthasarathy; Rachagani, Satyanarayana; Carmicheal, Joseph; Jahan, Rahat; Atri, Pranita; Venkata, Ramakanth C.; Gupta, Rohitesh; Marimuthu, Saravanakumar; Perumal, Naveenkumar; Rauth, Sanchita; Kaur, Sukhwinder; Mallya, Kavita; Smith, Lynette M.; Lele, Subodh M.; Ponnusamy, Moorthy P.; Nasser, Mohd W.; Salgia, Ravi; Batra, Surinder K.; and Ganti, Apar Kishor, "ST6GalNAc-I Promotes Lung Cancer Metastasis by Altering MUC5AC Sialylation" (2021). Journal Articles: Biochemistry & Molecular Biology. 139.
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