Dataset Information

Elucidation of Functional Roles of Sialic Acids in Cancer Migration.

ABSTRACT: Sialic acids (SA), negatively charged nine-carbon sugars, have long been implicated in cancer metastasis since 1960's but its detailed functional roles remain elusive. We present a computational analysis of transcriptomic data of cancer vs. control tissues of eight types in TCGA, aiming to elucidate the possible reason for the increased production and utilization of SAs in cancer and their possible driving roles in cancer migration. Our analyses have revealed for all cancer types: (1) the synthesis and deployment enzymes of SAs are persistently up-regulated throughout the progression for all but one cancer type; and (2) gangliosides, of which SAs are part, tend to converge to specific types that allow SAs to pack at high densities on cancer cell surface as a cancer advances. Statistical and modeling analyses suggest that (i) a highly plausible reason for the increased syntheses of SAs is to produce net protons, used for neutralizing the OH- persistently generated by elevated intracellular iron metabolism coupled with chronic inflammation in cancer tissues; (ii) the level of SA accumulation on cancer cell surface strongly correlates with the stage of cancer migration, as well as multiple migration-related characteristics such as altered cell-cell adhesion, mechanical stress, cell protrusion, and contraction; and (iii) the pattern of SA deployment correlates with the 5-year survival rate of a cancer type. Overall, our study provides strong evidence for that the continuous accumulation of SAs on cancer cell surface gives rise to increasingly stronger cell-cell repulsion due to their negative charges, leading to cell deformation by electrostatic force-induced mechanical compression, which is known to be able to drive cancer cell migration established by recent studies.

SUBMITTER: Sun H

PROVIDER: S-EPMC7137995 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Elucidation of Functional Roles of Sialic Acids in Cancer Migration.

Sun Huiyan H Zhou Yi Y Jiang Hongyang H Xu Ying Y

Frontiers in oncology 20200331

Sialic acids (SA), negatively charged nine-carbon sugars, have long been implicated in cancer metastasis since 1960's but its detailed functional roles remain elusive. We present a computational analysis of transcriptomic data of cancer vs. control tissues of eight types in TCGA, aiming to elucidate the possible reason for the increased production and utilization of SAs in cancer and their possible driving roles in cancer migration. Our analyses have revealed for all cancer types: (1) the synthe ...[more]

PMID: 32296639

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Project description:Rotaviruses (RVs) are a significant cause of severe diarrheal illness in infants and young animals, including pigs. Group C rotavirus (RVC) is an emerging pathogen increasingly reported in pigs and humans worldwide, and is currently recognized as the major cause of gastroenteritis in neonatal piglets that results in substantial economic losses to the pork industry. However, little is known about RVC pathogenesis due to the lack of a robust cell culture system, with the exception of the RVC Cowden strain. Here, we evaluated the permissiveness of porcine crypt-derived 3D and 2D intestinal enteroid (PIE) culture systems for RVC infection. Differentiated 3D and 2D PIEs were infected with porcine RVC (PRVC) Cowden G1P[1], PRVC104 G3P[18], and PRVC143 G6P[5] virulent strains, and the virus replication was measured by qRT-PCR. Our results demonstrated that all RVC strains replicated in 2D-PIEs poorly, while 3D-PIEs supported a higher level of replication, suggesting that RVC selectively infects terminally differentiated enterocytes, which were less abundant in the 2D vs. 3D PIE cultures. While cellular receptors for RVC are unknown, target cell surface carbohydrates, including histo-blood-group antigens (HBGAs) and sialic acids (SAs), are believed to play a role in cell attachment/entry. The evaluation of the selective binding of RVCs to different HBGAs revealed that PRVC Cowden G1P[1] replicated to the highest titers in the HBGA-A PIEs, while PRVC104 or PRVC143 achieved the highest titers in the HBGA-H PIEs. Further, contrasting outcomes were observed following sialidase treatment (resulting in terminal SA removal), which significantly enhanced Cowden and RVC143 replication, but inhibited the growth of PRVC104. These observations suggest that different RVC strains may recognize terminal (PRVC104) as well as internal (Cowden and RVC143) SAs on gangliosides. Finally, several cell culture additives, such as diethylaminoethyl (DEAE)-dextran, cholesterol, and bile extract, were tested to establish if they could enhance RVC replication. We observed that only DEAE-dextran significantly enhanced RVC attachment, but it had no effect on RVC replication. Additionally, the depletion of cellular cholesterol by MβCD inhibited Cowden replication, while the restoration of the cellular cholesterol partially reversed the MβCD effects. These results suggest that cellular cholesterol plays an important role in the replication of the PRVC strain tested. Overall, our study has established a novel robust and physiologically relevant system to investigate RVC pathogenesis. We also generated novel, experimentally derived evidence regarding the role of host glycans, DEAE, and cholesterol in RVC replication, which is critical for the development of control strategies.

Dataset Information

Elucidation of Functional Roles of Sialic Acids in Cancer Migration.

Publications

Elucidation of Functional Roles of Sialic Acids in Cancer Migration.

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