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.
Highlights
It has been observed that increased syntheses of sialic acids (SAs) are associated with cancer development and metastasis since 1960’s [1, 2], where Sialic acids (SA) are negatively charged nine-carbon sugars and generally serve as the capping molecules of cell-surface glycan, as part of plasma membrane-embedded gangliosides [3]
We present a computational study of transcriptomic data of SA related vs. migration related genes in cancer tissues of eight cancer types from the TCGA database [10]
We have examined the key genes involved in SA synthesis (CMAS) and degradation (NEU1)
Summary
It has been observed that increased syntheses of sialic acids (SAs) are associated with cancer development and metastasis since 1960’s [1, 2], where SAs are negatively charged nine-carbon sugars and generally serve as the capping molecules of cell-surface glycan, as part of plasma membrane-embedded gangliosides [3]. Very little has been established regarding if they may play roles in creating mechanical compression within cancer tissues, knowing their negative charges and being increasingly placed on cell surface, possibly resulting in increasingly stronger cell-cell repulsion, while mechanical pressure has been widely observed in cancer tissues but largely attributed to the confined space for growing tumors [6, 7]
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