The glycosyltransferase ST6Gal-I is enriched in cancer stem-like cells in colorectal carcinoma and contributes to their chemo-resistance

Abstract

Purpose

Presence of cancer stem cells (CSCs) contributes to tumor outgrowth, chemo-resistance and relapse in some cancers including colorectal carcinoma (CRC). The current characterization methods of CSCs in CRC only allows enrichment of CSCs but not their purification. Recent reports showed that ST6 beta-galactoside alpha-2,6-sialyltransferase 1 (ST6Gal-I) plays an essential role in protecting tumor cells against harsh environment like oxidative stress and nutrient deprivation. Therefore, whether ST6Gal-I may be highly expressed in CSCs or whether it may enhance resistance of tumor cells to chemotherapy deserves exploration.

Method

ST6Gal-I levels were determined in CRC specimens, compared to paired normal colorectal tissue, and examined in CD133+ vs CD133− CRC cells, and CD44+ vs CD44− CRC cells. ST6Gal-I levels and their association with patient survival were examined. In vivo, 2 CRC cell lines Caco-2 and SW48 were transduced with two lentiviruses, one lentivirus carrying a green fluorescent protein reporter and a luciferase reporter under a cytomegalovirus promoter to allow tracing tumor cells by both fluorescence and luciferase activity, and one lentivirus carrying a nuclear red fluorescent protein under the control of ST6Gal-I promoter to allow separation of ST6Gal-I+ vs ST6Gal-I− CRC cells. Tumor sphere formation, resistance to fluorouracil-induced apoptosis, and frequency of tumor formation after serial adoptive transplantation were done on ST6Gal-I+ vs ST6Gal-I− CRC cells.

Result

ST6Gal-I levels were significantly upregulated in clinically obtained CRC specimens, compared to paired normal colorectal tissue. Poorer patient survival was detected in ST6Gal-I-high CRC, compared to ST6Gal-I-low subjects. Higher levels of ST6Gal-I were detected in CD133+ CRC cells than CD133− CRC cells, and in CD44+ CRC cells than in CD44− CRC cells. Compared to ST6Gal-I− CRC cells, ST6Gal-I+ CRC cells generated significantly more tumor spheres in culture, were more resistant to fluorouracil-induced apoptosis likely through upregulating cell autophagy, and generated tumor more frequently after serial adoptive transplantation.

Conclusion

ST6Gal-I may be highly expressed in the cancer stem-like cells in CRC and enhances cancer cell resistance to chemotherapy.

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