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Interleukin-18 (IL-18) is a proinflammatory cytokine that primarily stimulates the Th1 immune response. IL-18 exhibits anticancer activity and has been evaluated in clinical trials as a potential cancer treatment. However, evidence suggests that it may also facilitate the development and progression of some cancers. So far, the impact of IL-18 on papillary thyroid cancer (PTC) has not been investigated. In this study, we found that the expression of IL-18 was significantly increased in PTC compared to normal thyroid tissue. Elevated IL-18 expression was closely associated with lymphovascular invasion and lymph node metastases. Furthermore, compared to PTC patients with no nodal metastasis, serum IL-18 levels were slightly increased in patients with 1–4 nodal metastases and significantly elevated in patients with 5 or more nodal metastases. The pro-metastatic effect of IL-18 may be attributed to the simultaneous increase in the expression of S100A10, a known factor that is linked to nodal metastasis in PTC. In addition, the activation of several pathways, such as the intestinal immune network for lgA production and Staphylococcus aureus infection, may be involved in the metastasis process. Taken together, IL-18 may trigger pro-metastatic activity in PTC. Therefore, suppressing the function of IL-18 rather than enhancing it appears to be a reasonable strategy for treating aggressive PTC. [ABSTRACT FROM AUTHOR]

The prefrontal cortex (PFC) is a key neural node mediating behavioral responses to stress and the actions of ketamine, a fast-acting antidepressant. The molecular mechanisms underlying these processes, however, are not fully understood. Our recent study revealed a pivotal role of hippocampal Ahnak as a regulator of cellular and behavioral adaptations to chronic stress. However, despite its significant expression in the PFC, the contribution of cortical Ahnak to behavioral responses to stress and antidepressants remains unknown. Here, using a mouse model for chronic social stress, we find that Ahnak expression in the PFC is significantly increased in stress-resilient mice and positively correlated with social interaction after stress exposure. Conditional deletion of Ahnak in the PFC or forebrain glutamatergic neurons facilitates stress susceptibility, suggesting that Ahnak is required for behavioral resilience. Further supporting this notion, Ahnak expression in the PFC is increased after the administration of ketamine or its metabolite (2R, 6R)-hydroxynorketamine (HNK). Moreover, Ahnak deletion in forebrain glutamatergic neurons blocks the restorative behavioral effects of ketamine or HNK in stress-susceptible mice. This forebrain excitatory neuronspecific Ahnak deletion reduces the frequency of mini excitatory postsynaptic currents in layer II/III pyramidal neurons, suggesting that Ahnak may induce its behavioral effects via modulation of glutamatergic transmission in the PFC. Altogether, these data suggest that Ahnak in glutamatergic PFC neurons may be critical for behavioral resilience and antidepressant actions of ketamine or HNK in chronic social stress-exposed mice. [ABSTRACT FROM AUTHOR]

Solute carrier organic anion transporter family member 2A1 (SLCO2A1) is a prostaglandin (PG) transporter and serves as the osmosensitive ATP-permeable maxi-anion channel (Maxi-Cl). Since a heterotetrameric complex of annexin A2 (ANXA2) and S100A10 is obligatory for the channel activity, the present study aimed to determine if they regulate SLCO2A1-mediated PG transport. This study examined PGE2 uptake and ATP release in Anxa2 and/or S100a10 knockout (KO) murine breast C127 cells. Deletion of Slco2a1 decreased PGE2-d4 uptake by wild-type (WT) cells in an isotonic medium (290 mosmol/kgH2O). Decreased osmolarity (135 mosmol/kgH2O) stimulated ATP release but did not affect PGE2 uptake kinetics, showing Km (1,280 nM) and Vmax (10.38 pmol/15 s/mg protein) similar to those in isotonic medium (1,227 nM and 10.65 pmol/15 s/mg protein), respectively, in WT cells. Deletion of Anxa2 associated with loss of S100a10 diminished SLCO2A1-mediated ATP release and uncompetitively inhibited PGE2 uptake with lowered Km (376 nM) and Vmax (2.59 pmol/15 s/mg protein). Moreover, the immunoprecipitation assay confirmed the physical interaction of ANXA2 with SLCO2A1 in WT cells. Enforcement of ANXA2 expression to Anxa2 KO cells partially restored PGE2 uptake and increased Km (744.3 nM) and Vmax (9.07 pmol/15 s/mg protein), whereas the uptake clearance (Vmax/Km) did not change much regardless of ANXA2 expression. These results suggest that an ANXA2/S100A10 complex modulates PG transport activity but osmolality has little effect on it; therefore, the bound form of SLCO2A1, which functions as a PG transporter and Maxi-Cl, may exist regardless of changes in the cell volume. NEW & NOTEWORTHY: A previous study indicated that the ANXA2/S100A10 complex represents the regulatory component of SLCO2A1-mediated Maxi-Cl channel activity. The present study showed that apparent PGE2 uptake by C127 cells was osmoinsensitive and uncompetitively inhibited by loss of ANXA2 expression, demonstrating that ANXA2 is a regulatory factor of SLCO2A1-mediated PG transport activity. [ABSTRACT FROM AUTHOR]

Tumor-derived exosomes bind to organ resident cells, activating S100 molecules during the remodeling of the local immune microenvironment. However, little is known regarding how organ resident cell S100A10 mediates cancer metastatic progression. Here, we provided evidence that S100A10 plays an important role in regulating the lung immune microenvironment and cancer metastasis. S100A10-deficient mice reduced cancer metastasis in the lung. Furthermore, the activation of S100A10 within lung fibroblasts via tumor-derived exosomes increased the expression of CXCL1 and CXCL8 chemokines, accompanied by the myeloid-derived suppressor cells (MDSCs) recruitment. S100A10 inhibitors such as 1-Substituted-4-Aroyl-3-hydroxy-5-Phenyl-1 H-5-pyrrol-2(5 H)-ones inhibit lung metastasis in vivo. Our findings highlight the crucial role of S100A10 in driving MDSC recruitment in order to remodel the lung immune microenvironment and provide potential therapeutic targets to block cancer metastasis to the lung.

In various epithelial tissues, the epithelial monolayer acts as a barrier. To fulfill its function, the structural integrity of the epithelium is tightly controlled. When normal epithelial cells detach from the basal substratum and delaminate into the apical lumen, the apically extruded cells undergo apoptosis, which is termed anoikis. In contrast, transformed cells often become resistant to anoikis and able to survive and grow in the apical luminal space, leading to the formation of multilayered structures, which can be observed at the early stage of carcinogenesis. However, the underlying molecular mechanisms still remain elusive. In this study, we first demonstrate that S100A10 and ANXA2 (Annexin A2) accumulate in apically extruded, transformed cells in both various cell culture systems and murine epithelial tissues in vivo. ANXA2 acts upstream of S100A10 accumulation. Knockdown of ANXA2 promotes apoptosis of apically extruded RasV12-transformed cells and suppresses the formation of multilayered epithelia. In addition, the intracellular reactive oxygen species (ROS) are elevated in apically extruded RasV12 cells. Treatment with ROS scavenger Trolox reduces the occurrence of apoptosis of apically extruded ANXA2-knockdown RasV12 cells and restores the formation of multilayered epithelia. Furthermore, ROS-mediated p38MAPK activation is observed in apically delaminated RasV12 cells, and ANXA2 knockdown further enhances the p38MAPK activity. Moreover, the p38MAPK inhibitor promotes the formation of multilayered epithelia of ANXA2-knockdown RasV12 cells. These results indicate that accumulated ANXA2 diminishes the ROS-mediated p38MAPK activation in apically extruded transformed cells, thereby blocking the induction of apoptosis. Hence, ANXA2 can be a potential therapeutic target to prevent multilayered, precancerous lesions. [ABSTRACT FROM AUTHOR]

S100A10 (p11, annexin II light chain, calpactin light chain) is a multifunctional protein with a wide range of physiological activity. S100A10 is unique among the S100 family members of proteins since it does not bind to Ca2+, despite its sequence and structural similarity. This review focuses on studies highlighting the structure, regulation, and binding partners of S100A10. The binding partners of S100A10 were collated and summarized. [ABSTRACT FROM AUTHOR]

Abstract Background Hepatocellular carcinoma (HCC) is one of the most common human cancers with poor prognosis in the world. HCC has become the second leading cause of cancer-related death in China. It is urgent to identify novel biomarker and valid target to effectively diagnose, treat or predict the prognosis of HCC. It has been reported that S100A family is closely related to cell proliferation and migration of different cancers. However, the values of S100As in HCC remain to be further analyzed. Methods We investigated the transcriptional and translational expression of S100As, as well as the value of this family in HCC patients from the various databases. Results S100A10 was most relevant to HCC. Conclusions The results from HCC patients’ tissues and different cells also confirmed the role of S100A10 in HCC. Furthermore, we proved that S100A10 could influenced the cell proliferation of HCC cells via ANXA2/Akt/mTOR pathway. However, it would appear that the relationship between S100A10 and HCC is complex and requires more research.

ABSTRACTAnnexin A2 is a Ca2+ regulated protein belonging to the Annexin family and is found in the cytoplasm and cell membrane. It can exist in a monomeric form or in a heterotetrameric form with the S100A10 dimer. The research on Annexin A2 in tumours is currently active, and studies on its role in pathogen infection are increasing. Annexin A2 plays a crucial role in the life cycle of viruses by mediating adhesion, internalization, uncoating, transport, and release. In the case of parasites, bacteria, mycoplasma, fungi, and other pathogens, Annexin A2 binds to the ligand on the pathogen, which mediates the pathogen’s adhesion to the host cell, ultimately leading to infection and damage to the host. Furthermore, some studies have developed biological or chemical drugs that target Annexin A2, which have demonstrated promising anti-infective effects. Thus, targeting Annexin A2 may present a promising therapeutic approach for the treatment of diverse infectious diseases. In summary, this paper provides an overview of Annexin A2 and its role in various pathogens. It highlights its regulation of pathogen infection and its potential as a therapeutic target for the treatment of infectious diseases.

Annexin A2 (A2) is a member of the Annexin family, which contains Ca2+‐regulated phospholipid‐binding proteins. Annexins associate with S100 proteins to form heterotetramers. The A2/S100A10 heterotetramer (A2t) is the most extensively studied of these heterotetramers. It induces membrane microdomain formation, causes membrane budding, and facilitates proliferation of some cancers. In this work, the first molecular dynamics (MD) study on the complete A2t of 868 amino acids was performed. MD trajectories of more than 600 ns each were generated for complete A2t complexes with and without Ca2+ ions. The outward extension of membrane‐binding residues A2‐K279 and A2‐K281 was shown to be inhibited in the absence of Ca2+ as they were captured by Ca2+‐binding residue D322. F‐actin binding residue A2‐D339 was observed to occupy either an exposed or buried state in the absence of Ca2+, while it only occupied the buried state in the presence of Ca2+. The observed motions of the A2t subunits are highly organized with a strongly correlated central region which is negatively correlated with the periphery of the complex. The central region contains the S100A10 (p11) dimer, A2‐N, and A2‐I, while the periphery contains A2‐II, A2‐III, and A2‐IV. Novel interactions between A2 and p11 were identified. A2 residues outside of A2‐N (K80, R77, E82, and R145) had strong interactions with p11. Residue R145 of A2 may have a significant effect on the dynamics of the system, with its interaction resulting in asymmetric motions of A2. The presented results provide novel insights to inform future experimental studies. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is one of the most common human cancers with poor prognosis in the world. HCC has become the second leading cause of cancer-related death in China. It is urgent to identify novel biomarker and valid target to effectively diagnose, treat or predict the prognosis of HCC. It has been reported that S100A family is closely related to cell proliferation and migration of different cancers. However, the values of S100As in HCC remain to be further analyzed. Methods: We investigated the transcriptional and translational expression of S100As, as well as the value of this family in HCC patients from the various databases. Results: S100A10 was most relevant to HCC. Conclusions: The results from HCC patients' tissues and different cells also confirmed the role of S100A10 in HCC. Furthermore, we proved that S100A10 could influenced the cell proliferation of HCC cells via ANXA2/Akt/mTOR pathway. However, it would appear that the relationship between S100A10 and HCC is complex and requires more research. [ABSTRACT FROM AUTHOR]

Introduction: Although many studies have demonstrated the existing neurological symptoms in COVID-19 patients, the mechanisms are not clear until now. This study aimed to figure out the critical molecular and immune infiltration situations in the brain of elderly COVID-19 patients. Methods: GSE188847 was used for the differential analysis, WGCNA, and immune infiltration analysis. We also performed GO, KEGG, GSEA, and GSVA for the enrich analysis. Results: 266 DEGs, obtained from the brain samples of COVID-19 and non-COVID-19 patients whose ages were over 70 years old, were identified. GO and KEGG analysis revealed the enrichment in synapse and neuroactive ligandreceptor interaction in COVID-19 patients. Further analysis found that asthma and immune system signal pathways were significant changes based on GSEA and GSVA. Immune infiltration analysis demonstrated the imbalance of CD8+ T cells, neutrophils, and HLA. The MEpurple module genes were the most significantly different relative to COVID-19. Finally, RPS29, S100A10, and TIMP1 were the critical genes attributed to the progress of brain damage. Conclusion: RPS29, S100A10, and TIMP1 were the critical genes in the brain pathology of COVID-19 in elderly patients. Our research has revealed a new mechanism and a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite the advance in therapeutic strategy, the prognosis of pancreatic ductal adenocarcinoma (PDAC) is still unsatisfactory, with a 5-year survival rate of less than 9%. As a member of the S100 protein family, S100A10 has been identified as an oncogene in multiple cancers. In PDAC, S100A10 has been reported to be not only up-regulated in tumor tissues but also associated with survival outcomes. However, the specific function of S100A10 in PDAC is still unknown. Here, we suggest that S100A10 promotes PDAC cells proliferation, migration, and adhesion by activating JNK/LAMB3-LAMC2 axis in vitro and accelerates pancreatic tumor growth in vivo, indicating that S100A10 may be a potential therapeutic target for PDAC patients. Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors, characterized by diagnosis at an advanced stage and a poor prognosis. As a member of the S100 protein family, S100A10 regulates multiple biological functions related to cancer progression and metastasis. However, the role of S100A10 in PDAC is still not completely elucidated. In this study, we reported that S100A10 was significantly up-regulated in PDAC tissue and associated with a poor prognosis by integrated bioinformatic analysis and human PDAC tissue samples. In vitro, down-regulation of S100A10 reduced the proliferation, migration, and adhesion of PDAC cell lines, whereas up-regulation of S100A10 showed the opposite effect. Furthermore, LAMB3 was proved to be activated by S100A10 using RNA-sequencing and western blotting. The effect of LAMB3 on the proliferation, migration, and adhesion of PDAC cells was similar to that of S100A10. Up-regulation or down-regulation of LAMB3 could reverse the corresponding effect of S100A10. Moreover, we validated S100A10 activates LAMB3 through the JNK pathway, and LAMB3 was further proved to interact with LAMC2. Mice-bearing orthotopic pancreatic tumors showed that S100A10 knocked-down PANC-1 cells had a smaller tumor size than the control group. In conclusion, S100A10 promotes PDAC cells proliferation, migration, and adhesion through JNK/LAMB3-LAMC2 axis. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) usually results in loss or reduction in motor and sensory functions. Despite extensive research, no available therapy can restore the lost functions after SCI. Reactive astrocytes play a pivotal role in SCI. Rho kinase inhibitors have also been shown to promote functional recovery of SCI. However, the role of Rho kinase inhibitors in reactive astrocytic phenotype switch within SCI remains largely unexplored. In this study, astrocytes were treated with proinflammatory cytokines and/or the Rho kinase inhibitor Y27632. Concomitantly the phenotype and morphology of astrocytes were examined. Meanwhile, the SCI model of SD rats was established, and nerve functions were evaluated following treatment with Y27632. Subsequently, the number of A1 astrocytes in the injured area was observed and analyzed. Eventually, the expression levels of nuclear factor kappa B (NF-κB), C3, and S100A10 were measured. The present study showed that the Rho kinase inhibitor Y27632 improved functional recovery of SCI and elevated the proliferation and migration abilities of the astrocytes. In addition, Y27632 treatment initiated the switch of astrocytes morphology from a flattened shape to a process-bearing shape and transformed the reactive astrocytes A1 phenotype to an A2 phenotype. More importantly, further investigation suggested that Y27632 was actively involved in promoting the functional recovery of SCI in rats by inhabiting the ROCK/NF-κB/C3 signaling pathway. Together, Rho kinase inhibitor Y27632 effectively promotes the functional recovery of SCI by shifting astrocyte phenotype and morphology. Furthermore, the pro-regeneration event is strongly associated with the ROCK/NF-κB/C3 signal pathway. [ABSTRACT FROM AUTHOR]

Aberrant chondrocyte apoptosis and inflammation are the most critical causes of osteoarthritis (OA) development. This study was designed to demonstrate the relationship between S100A10 and OA. In this study, S100A10 was overexpressed or silenced in rat chondrocytes. Cell viability, apoptosis, reactive oxidative species (ROS), and calcium ion detection were assessed using Cell Counting Kit‐8 assay and flow cytometry. The levels of key oxidation‐related enzymes and tumor necrosis factor‐alpha (TNF‐α) were quantified using enzyme‐linked immunosorbent assay, quantitative polymerase chain reaction, and Western blotting. S100A10 was highly expressed in patients with OA and positively correlated with TNF‐α level. Knockdown of S100A10 effectively counteracted TNF‐α‐induced ROS level, apoptosis, and calcium level and associated with decreased inflammation‐related metalloproteinase 1 (MMP1), MMP13, and nuclear necrosis factor‐kappa B (NF‐κB)‐p65 and increased survivin and cytoplasmic NF‐κB‐p65. Overexpression of S100A10 had an effect similar to TNF‐α, which was significantly counteracted by pyrrolidine dithiocarbamate, an NF‐κB inhibitor, or verapamil, a calcium‐channel blocker. S100A10 contributed to chondrocyte apoptosis through the ROS/NF‐κB pathway. This study has established the relationship between S100A10 and the NF‐κB pathway, thus providing novel perspectives for exploring S100A10 functions. [ABSTRACT FROM AUTHOR]

Targeted therapy based on BRD4 and MYC shows promise due to their well-researched oncogenic functions in cancer, but their tumor-suppressive roles are less understood. In this study, we employ a systematic approach to delete exons that encode the low-complexity domain (LCD) of BRD4L in cells by using CRISPR–Cas9. In particular, the deletion of exon 14 (BRD4–E14) results in cellular morphological changes towards spindle-shaped and loosely packed. BRD4–E14 deficient cells show increased cell migration and reduced cell adhesion. The expression of S100A10 was significantly increased in cells lacking E14. BRD4L binds with MYC via the E14-encoded region of the LCD to inhibit the expression of S100A10. In cancer tissues, there is a positive correlation between BRD4 and MYC, while both of these proteins are negatively associated with S100A10 expression. Finally, knocking out the BRD4–E14 region or MYC promotes tumor growth in vivo. Together, these data support a tumor-suppressive role of BRD4L and MYC in some contexts. This discovery emphasizes the significance of a discreetly design and precise patient recruitment in clinical trials that testing cancer therapy based BRD4 and MYC. • Knockout BRD4L-E14 or MYC promotes tumor development in vivo. • BRD4L and MYC promotes cellular adhesion. • BRD4L and MYC negatively regulate S100A10 expression. • BRD4L binds with MYC via exon 14 of BRD4L. [ABSTRACT FROM AUTHOR]

S100A10 (p11, annexin II light chain, calpactin light chain) is a multifunctional protein with a wide range of physiological activity. S100A10 is unique among the S100 family members of proteins since it does not bind to Ca2+, despite its sequence and structural similarity. This review focuses on studies highlighting the structure, regulation, and binding partners of S100A10. The binding partners of S100A10 were collated and summarized.

Previous studies have demonstrated the role of S100A10 in the progression of several tumors; however, few studies have investigated its immunological characteristics in adult gliomas. In this study, we systematically explored its biological features and clinical significance in adult gliomas. Altogether, 325 glioma cases from the Chinese Glioma Genome Atlas and 699 glioma cases from The Cancer Genome Atlas were included as the training and validation cohorts. R software was used for data analysis and mapping using the RNA sequencing data from these cases. One-way analysis of variance and Student's t-test were used to assess the differences between the groups. Differences were considered statistically significant at P < 0.05. We found that S100A10 was remarkably highly expressed in high-grade glioma, isocitrate dehydrogenase wild type, 1p19q noncodeletion type, O6-methylguanine-DNA methyltransferase promoter unmethylation type, and mesenchymal-like molecular subtype. S100A10 specifically and sensitively indicates the mesenchymal-like molecular subtype. Upregulated S100A10 levels were independently correlated with poor survival. S100A10-related biological processes in gliomas mainly concentrate on immunoreaction and inflammatory response. We then proved that S100A10 was positively related to most inflammatory metagenes, except IgG, including HCK, LCK, MHC II, STAT1, and interferon. More importantly, the levels of glioma-infiltrating immune cells were positively associated with the expression of S100A10, especially in tumor-related macrophages, regulatory T cells, and myeloid-derived suppressor cells. S100A10 is closely related to malignant pathological subtypes, worse prognosis, and immunosuppressive immune cell infiltration in adult gliomas, making it a promising biomarker and potential target in the diagnosis, treatment, and prognostic assessment of gliomas. [ABSTRACT FROM AUTHOR]

Tumor-derived exosomes bind to organ resident cells, activating S100 molecules during the remodeling of the local immune microenvironment. However, little is known regarding how organ resident cell S100A10 mediates cancer metastatic progression. Here, we provided evidence that S100A10 plays an important role in regulating the lung immune microenvironment and cancer metastasis. S100A10-deficient mice reduced cancer metastasis in the lung. Furthermore, the activation of S100A10 within lung fibroblasts via tumor-derived exosomes increased the expression of CXCL1 and CXCL8 chemokines, accompanied by the myeloid-derived suppressor cells (MDSCs) recruitment. S100A10 inhibitors such as 1-Substituted-4-Aroyl-3-hydroxy-5-Phenyl-1 H-5-pyrrol-2(5 H)-ones inhibit lung metastasis in vivo. Our findings highlight the crucial role of S100A10 in driving MDSC recruitment in order to remodel the lung immune microenvironment and provide potential therapeutic targets to block cancer metastasis to the lung., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Background: Excessive inflammation has been implicated in the immunopathogenesis of coronavirus disease 2019 (COVID-19). In the current study, the involvement of S100 calcium binding protein S100A4, S100A9, and S100A10 in the inflammatory settings of COVID-19 patients were evaluated. Methods: Peripheral blood samples were obtained from 65 COVID-19 subjects and 50 healthy controls. From the blood samples, RNA was extracted and cDNA was synthesized, and then the mRNA expression levels of S100A4, S100A9, and S100A10 were measured by Real-time PCR. Results: The mRNA expression of S100A4 (fold change [FC] = 1.45, P = 0.0011), S100A9 (FC = 1.47, P = 0.0013), and S100A10 (FC = 1.35, P = 0.0053) was significantly upregulated in COVID-19 patients than controls. The mRNA expression of S100A4 (FC = 1.43, P = 0.0071), (FC = 1.66, P = 0.0001), and S100A10 (FC = 1.63, P = 0.0003) was significantly upregulated in the severe COVID-19 subjects than mild-to-moderate subjects. There was a significant positive correlation between mRNA expression of S100A4 (ρ = 0.49, P = 0.030), S100A9 (ρ = 0.55, P = 0.009), and S100A10 (ρ = 0.39, P = 0.040) and d-dimer in the COVID-19 patients. The AUC for S100A4, S100A9, and S100A10 mRNAs were 0.79 (95% CI 0.66–0.92, P = 0.004), 0.80 (95% CI 0.67–0.93, P = 0.002), and 0.71 (95% CI 0.56–0.85, P = 0.010), respectively. Conclusions: S100A4, S100A9, and S100A10 play a role in the inflammatory conditions in COVID-19 patients and have potential in prognosis of severe form of COVID-19. Targeting these modules, hopefully, might confer a therapeutic tool in preventing sever symptoms in the COVID-19 patients. [ABSTRACT FROM AUTHOR]

Abstract Background Tumor budding (TB) and poorly differentiated clusters (PDCs) are a sequence of histologic findings that predict worse prognosis and node metastasis in colorectal cancer (CRC). TB and PDC (TB/PDC) are caused by cancer cell detachment and are distinguished by the number of cancer cells that constitute a cell cluster. In short, PDC is regarded as the previous step of TB. TB/PDC and epithelial-mesenchymal transition (EMT) are closely linked, but its pathogenic mechanisms are still unclear. S100A10, a member of the S100 protein family, forms a heterocomplex with annexin A2 (ANX A2) and then translocates to cell membrane from the cytoplasm and plays various roles in cell dynamics, including plasminogen activation. S100A10 is the activation modulator of the heterocomplex and promotes cell invasion. S100A10 is involved in the remodeling of both actin and extracellular matrix (ECM), which is also associated with EMT. Case presentation In two representative cases of conventional advanced CRC, we immunohistochemically examined S100A10 and ANX A2 expressions in which both TB and PDC were prominent. Both CRCs metastasized to multiple regional lymph nodes. In both cases, a membranous positivity for S100A10 was diffusely found in both tumor buds and PDCs and was observed in the tumor cells protruding toward the stroma, giving rise to TB/PDC. However, even in tumor glands with TB/PDC, the tumor cells with a smooth border around the stroma showed either cytoplasmic fine-granular expression or no positivity. The immunoreactivity for ANX A2 was almost the same as that for S100A10. In the main tumor components without TB/PDC, no distinct positivity was detected at their smooth borders. Conclusions During oncogenesis, membranous S100A10 has the potential to be related to TB of CRC. This may be due to plasminogen activation, actin remodeling, and interaction with an altered ECM. However, further study is required to confirm this hypothesis.

Abstract Background Ovarian cancer is the leading cause of gynecological cancer-related mortality. The novel oncogene S100A10 has been reported to be involved in cancer cell proliferation, invasion and metastasis. The role of S100A10 in ovarian cancer has not been well studied and the effect of S100A10 on chemotherapy remains unclear. The aims of the present study were to investigate the functional role of S100A10 in the progression and carboplatin sensitivity of ovarian cancer. Methods We examined the expression levels in tissues of S100A10 in 138 cases of ovarian cancer by IHC. To determine the functional roles of downregulated S100A10 in ovarian cancer, cell proliferation, colony formation, cell migration and invasion assays were performed. Chemoresistance was analyzed by apoptosis assay. A xenograft tumor model was established to confirm the role of S100A10 in carboplatin resistance in vivo. Using Western blot assays, we also explored the possible mechanisms of S100A10 in ovarian cancer. Results The results showed that increased expression of S100A10 was positively associated with carboplatin resistance (P

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors, characterized by diagnosis at an advanced stage and a poor prognosis. As a member of the S100 protein family, S100A10 regulates multiple biological functions related to cancer progression and metastasis. However, the role of S100A10 in PDAC is still not completely elucidated. In this study, we reported that S100A10 was significantly up-regulated in PDAC tissue and associated with a poor prognosis by integrated bioinformatic analysis and human PDAC tissue samples. In vitro, down-regulation of S100A10 reduced the proliferation, migration, and adhesion of PDAC cell lines, whereas up-regulation of S100A10 showed the opposite effect. Furthermore, LAMB3 was proved to be activated by S100A10 using RNA-sequencing and western blotting. The effect of LAMB3 on the proliferation, migration, and adhesion of PDAC cells was similar to that of S100A10. Up-regulation or down-regulation of LAMB3 could reverse the corresponding effect of S100A10. Moreover, we validated S100A10 activates LAMB3 through the JNK pathway, and LAMB3 was further proved to interact with LAMC2. Mice-bearing orthotopic pancreatic tumors showed that S100A10 knocked-down PANC-1 cells had a smaller tumor size than the control group. In conclusion, S100A10 promotes PDAC cells proliferation, migration, and adhesion through JNK/LAMB3-LAMC2 axis.

Long non-coding RNAs (lncRNAs) have been reported to play a crucial role in the pathogenesis of numerous cancers. However, the function of lncRNA KCNMB2-AS1 in bladder cancer (BC) remains unclear. In the present study, we aimed to explore the role and underlying mechanisms of KCNMB2-AS1 in bladder cancer progression. We found that lncRNA KCNMB2-AS1 was significantly upregulated both in BC tissues and cell lines, the expression level was highly correlated with pathological TNM stage. Functionally, knockdown of lncRNA KCNMB2-AS1 dramatically inhibited the proliferation, migration, and invasion and of BC cells in vitro , and suppressed tumor growth in vivo. Mechanistically, lncRNA KCNMB2-AS1 could function as a competitive endogenous RNA (ceRNA) through direct sponging miR-374a-3p, which regulated the expression of S100A10. In conclusion, our results demonstrated that lncRNA KCNMB2-AS1 can promote the progression of bladder cancer through regulation of miR-374a-3p/S100A10. [ABSTRACT FROM AUTHOR]

Our previous studies have confirmed that cobalt chloride (CoCl2) or chemoradiotherapy could induce the formation of polyploid tumor giant cells (PGCCs). Polyploid giant cancer cells are a special subpopulation of cancer cells that contribute to solid tumor heterogeneity. The size of PGCC was at least three times larger than regular diploid cancer cells. PGCCs have the properties of cancer stem cells (CSCs) and can express CSC markers CD44 and CD133. Daughter cells derived from PGCCs have strong proliferation, infiltration and migration abilities. However, the detailed molecular mechanism of daughter cells expressing mesenchymal phenotype and displaying strong abilities of proliferation and migration is unclear. As a plasminogen receptor, S100A10 which is closely associated with the invasion and metastasis of malignant tumors, was highly expressed in PGCCs with their daughter cells. In this study, CoCl2 was used to induce the formation of PGCCs in LoVo and HCT116 CRC cells. Cell functional experiments, co-immunoprecipitation, MG132 and ginkgolic acid treatment, western blot, and ChIP-Seq were used to identify the mechanism of S100A10 nuclear location. The proliferation and migration abilities of PGCCs and their daughter cells decreased significantly after S100A10 knockdown. In the control cells, S100A10 was mainly ubiquitinated, while in PGCCs and daughter cells, S100A10 was mainly SUMOylated, which was associated with S100A10 nuclear location. After SUMO1 was inhibited, the nuclear S100A10 in PGCCs and daughter cells decreased, and their proliferation and migration abilities significantly decreased. ChIP-Seq combined with real-time fluorescent quantitative PCR showed that S100A10 regulated the expression of neutrophil defensin 3 (DEFA3), receptor-type tyrosine-protein phosphatase N2 (PTPRN2), and rho guanine nucleotide exchange factor 18 (ARHGEF18), which were associated with actin dynamics and cytoskeleton remodeling. The expression of S100A10 in the nuclei and cytoplasm of rectal cancer after neoadjuvant chemoradiation (nCRT) and liver metastases increased compared with that in rectal cancer without nCRT. Taken together, the expression and nuclear localization of S100A10 modified by SUMOylation were associated with the high proliferation and migration of PGCCs and their daughter cells, and the differentiation, metastases, and relapse of CRCs by regulating the expression of ARHGEF18, PTPRN2, and DEFA3.

Long non-coding RNAs (lncRNAs) have been reported to play a crucial role in the pathogenesis of numerous cancers. However, the function of lncRNA KCNMB2-AS1 in bladder cancer (BC) remains unclear. In the present study, we aimed to explore the role and underlying mechanisms of KCNMB2-AS1 in bladder cancer progression. We found that lncRNA KCNMB2-AS1 was significantly upregulated both in BC tissues and cell lines, the expression level was highly correlated with pathological TNM stage. Functionally, knockdown of lncRNA KCNMB2-AS1 dramatically inhibited the proliferation, migration, and invasion and of BC cells in vitro, and suppressed tumor growth in vivo. Mechanistically, lncRNA KCNMB2-AS1 could function as a competitive endogenous RNA (ceRNA) through direct sponging miR-374a-3p, which regulated the expression of S100A10. In conclusion, our results demonstrated that lncRNA KCNMB2-AS1 can promote the progression of bladder cancer through regulation of miR-374a-3p/S100A10.

Hepatocarcinogenesis is a highly complicated process that is promoted by a series of oncogenes. Our study aims to identify novel oncogenes promoting hepatocellular carcinoma (HCC) by bioinformatic analysis and experimental validation. Here, we reported that S100 calcium binding protein A10 (S100A10) was screened out as a potential novel oncogene in HCC by integrated analysis of OEP000321 dataset and the Cancer Genome Atlas (TCGA)-Liver-Cancer data. Furthermore, S100A10 was highly expressed in HCC samples and observably associated with patients’ overall survival (OS). Overexpression of S100A10 in Hep3B and Huh-7 increased the cell proliferation, whereas downregulation of S100A10 in SK-Hep-1 and HepG2 cells reduced the cell viability to almost stop growing. In vivo tumor growth assays showed that S100A10-overexpressing Hep3B cells had a larger tumor size than control. Moreover, S100A10 overexpression promoted Hep3B cells migration and invasion, and S100A10 knockdown inhibited SK-Hep-1 cells migration and invasion, in vitro. In conclusion, it is demonstrated that S100A10 is a novel oncogene in HCC, indicating a possible novel therapeutic strategy of HCC.

Hepatocarcinogenesis is a highly complicated process that is promoted by a series of oncogenes. Our study aims to identify novel oncogenes promoting hepatocellular carcinoma (HCC) by bioinformatic analysis and experimental validation. Here, we reported that S100 calcium binding protein A10 (S100A10) was screened out as a potential novel oncogene in HCC by integrated analysis of OEP000321 dataset and the Cancer Genome Atlas (TCGA)-Liver-Cancer data. Furthermore, S100A10 was highly expressed in HCC samples and observably associated with patients' overall survival (OS). Overexpression of S100A10 in Hep3B and Huh-7 increased the cell proliferation, whereas downregulation of S100A10 in SK-Hep-1 and HepG2 cells reduced the cell viability to almost stop growing. In vivo tumor growth assays showed that S100A10-overexpressing Hep3B cells had a larger tumor size than control. Moreover, S100A10 overexpression promoted Hep3B cells migration and invasion, and S100A10 knockdown inhibited SK-Hep-1 cells migration and invasion, in vitro. In conclusion, it is demonstrated that S100A10 is a novel oncogene in HCC, indicating a possible novel therapeutic strategy of HCC. [ABSTRACT FROM AUTHOR]

• S100a10 inhibits the occurrence and development of ulcerative colitis. • S100a10-/- neutrophils had stronger function in secretion and synthesis of inflammatory factor. • S100a10 has no regulatory effect on the migration and phagocytic function of neutrophils. S100a10 is a member of the S100 family of proteins, which plays a key role in the depression and tumor metastasis. However, the role of S100a10 is unclear in ulcerative colitis. The effect of S100a10 was assessed using a murine ulcerative colitis model which was accompanied by parameters including body weight loss, disease activity index, histological score, colon weight and length. The quantity and role of immune cells was determined by flow cytometry and bone marrow chimeric mice. Neutrophils depletion, adoptive cell transfer and conditional knockout mice were used to ascertain which cells played the key role in ulcerative colitis. The function of neutrophils was evaluated by migration assay, phagocytosis assay, multiplex immunoassay and real-time PCR. In this study, our data showed that S100a10-/- mice were prone to ulcerative colitis induced by dextran sodium sulfate. Neutrophils number increased in colon of S100a10-/- mice after dextran sodium sulfate treatment significantly. Meanwhile, adoptive transfer of neutrophils from wild type mice partially decreased the susceptibility of S100a10-/- mice to dextran sodium sulfate. There was no difference in ulcerative colitis between the groups of S100a10-/- mice without neutrophils and wild type mice. Finally, we found that S100a10-/- neutrophils had stronger function in secretion and synthesis of inflammatory factor. In one word, these results suggest that S100a10 has a role in inhibiting the pathogenesis of ulcerative colitis through regulation of neutrophils function. [ABSTRACT FROM AUTHOR]

As a member of the S100 protein family, S100A10 has already been purified. However, its purity, or even yield, have often not been reported in the literature. To facilitate future biophysical experiments with S100A10, we aimed to obtain it at a purity of at least 95% in a reasonably large amount. Here, we report optimized conditions for the transformation, overexpression and purification of the protein. We obtained a purity of 97% and performed stability studies by circular dichroism. Our data confirmed that the S100A10 obtained is suitable for experiments to be performed at room temperature up to several days.

Abstract Background Annexin A2 is increased in serous ovarian cancer and plays an essential role in ovarian cancer invasion and metastasis. In combination with S100A10, annexin A2 plays an important role in the plasminogen activator system regulating plasmin production. The aim of this study was to investigate the potential utility of all-trans retinoid acid (ATRA), an inhibitor of the annexin A2-S100A10 signalling pathway, as a new therapeutic against serous ovarian cancer. Methods In this study we determined the effects of ATRA treatment (1-5 μM) on annexin A2 and S100A10 expression, plasmin activation, and the ability of ATRA to inhibit serous ovarian cancer cell survival, motility and invasion in vitro. We also employed an ex vivo tissue explant assay to assess response to ATRA treatment in serous ovarian cancers. Cryopreserved serous ovarian cancer tissues were cultured on gelatin sponges for 72 h with ATRA (1 μM). Effects on apoptosis and proliferation were assessed by immunohistochemistry using antibodies to cleaved caspase 3 or Ki67, respectively. Results Survival of serous ovarian cancer cells (OVCAR-3, OV-90, & OAW28) was significantly decreased by ATRA treatment (1-5 μM). ATRA (1 μM) also significantly decreased proliferation (Ki67 positivity, p = 0.0034), S100A10 protein levels (p = 0.0273), and increased cell apoptosis (cleaved caspase-3 positivity, p = 0.0024) in serous ovarian cancer tissues using the ex vivo tissue explant assay. In OAW28 cells, reduced cell survival following ATRA treatment was associated with a reduction of S100A10 mRNA and protein levels, S100A10 and annexin A2 membrane localization, plasmin generation, motility and invasion. In contrast, ATRA inhibited OV-90 cell survival and invasion but did not affect plasmin activation or S100A10 and annexin A2 expression or membrane localization. Conclusions These findings suggest that ATRA inhibits serous ovarian cancer proliferation and invasion via both S100A10 dependant and S100A10 independent mechanisms. Our results show that ATRA has promising potential as a novel therapy against serous ovarian cancer that warrants further evaluation.

Pancreatic cancer is arguably the deadliest cancer type. The efficacy of current therapies is often hindered by the inability to predict patient outcome. As such, the development of tools for early detection and risk prediction is key for improving outcome and quality of life. Here, we introduce the plasminogen receptor S100A10 as a novel predictive biomarker and a driver of pancreatic tumor growth and invasion. We demonstrated that S100A10 mRNA and protein are overexpressed in human pancreatic tumors compared to normal ducts and nonductal stroma. S100A10 mRNA and methylation status were predictive of overall survival and recurrence‐free survival across multiple patient cohorts. S100A10 expression was driven by promoter methylation and the oncogene KRAS. S100A10 knockdown reduced surface plasminogen activation, invasiveness, and in vivo growth of pancreatic cancer cell lines. These findings delineate the clinical and functional contribution of S100A10 as a biomarker in pancreatic cancer.

Abstract Background Deer antlers are bony structures that re-grow at very high rates, making them an attractive model for studying rapid bone regeneration. Methods To identify the genes that are involved in this fast pace of bone growth, an in vitro RNA-seq model that paralleled the sharp differences in bone growth between deer antlers and humans was established. Subsequently, RNA-seq (> 60 million reads per library) was used to compare transcriptomic profiles. Uniquely expressed deer antler proliferation as well as mineralization genes were identified via a combination of differential gene expression and subtraction analysis. Thereafter, the physiological relevance as well as contributions of these identified genes were determined by immunofluorescence, gene overexpression, and gene knockdown studies. Results Cell characterization studies showed that in vitro-cultured deer antler-derived reserve mesenchyme (RM) cells exhibited high osteogenic capabilities and cell surface markers similar to in vivo counterparts. Under identical culture conditions, deer antler RM cells proliferated faster (8.6–11.7-fold increase in cell numbers) and exhibited increased osteogenic differentiation (17.4-fold increase in calcium mineralization) compared to human mesenchymal stem cells (hMSCs), paralleling in vivo conditions. Comparative RNA-seq identified 40 and 91 previously unknown and uniquely expressed fallow deer (FD) proliferation and mineralization genes, respectively, including uhrf1 and s100a10. Immunofluorescence studies showed that uhrf1 and s100a10 were expressed in regenerating deer antlers while gene overexpression and gene knockdown studies demonstrated the proliferation contributions of uhrf1 and mineralization capabilities of s100a10. Conclusion Using a simple, in vitro comparative RNA-seq approach, novel genes pertinent to fast bony antler regeneration were identified and their proliferative/osteogenic function was verified via gene overexpression, knockdown, and immunostaining. This combinatorial approach may be applicable to discover unique gene contributions between any two organisms for a given phenomenon-of-interest.

S100 calcium-binding protein A10 (S100A10) is crucially involved in the tumorigenesis of multiple malignant tumors. Reprogrammed glucose metabolism is emerging as a hallmark of various human cancers. However, the function of S100A10 in aerobic glycolysis is unclear. The expression of S100A10 was analyzed using the Oncomine database, Gene Expression Profiling Interactive Analysis (GEPIA), The Cancer Genome Atlas (TCGA), and the UALCAN cancer database. Prognostic analysis was performed using the Kaplan–Meier Plotter. The correlation between S100A10 and key glycolytic factors was assessed by GEPIA. The glycolysis level was examined by determining glucose consumption, lactate production, adenosine triphosphate production, cellular oxygen consumption rate, and extracellular acidification rate. Cell apoptosis was investigated by flow cytometry. Colony formation and BrdU assays were performed to detect cell proliferation. A subcutaneous xenograft mouse model was established to evaluate the effects of S100A10 in vivo. Gene Set Enrichment Analysis and western blotting were performed to explore the downstream signaling pathway. S100A10 was significantly upregulated in gastric cancer. Its expression was associated with poor survival. S100A10 increased glucose consumption, lactate production, and the switch from oxidative phosphorylation to aerobic glycolysis. S100A10 promoted malignant proliferation and suppressed cell apoptosis in gastric cancer. S100A10 activated the mTOR pathway by interacting with annexin A2 (ANXA2) to accelerate tumor glycolysis, resulting in tumor malignant progression. S100A10 contributed to aerobic glycolysis and accelerated malignant growth by modulating the Src/ANXA2/AKT/mTOR signaling pathway. Thus, S100A10 may have pivotal roles in gastric cancer.

Metastatic progression remains the major cause of death in human breast cancer. Cancer cells with cancer stem cell (CSC) properties drive initiation and growth of metastases at distant sites. We have previously established the breast cancer patient‐derived tumor xenograft (PDX) mouse model in which CSC marker CD44+ cancer cells formed spontaneous microscopic metastases in the liver. In this PDX mouse, the expression levels of S100A10 and its family proteins were much higher in the CD44+ cancer cells metastasized to the liver than those at the primary site. Knockdown of S100A10 in breast cancer cells suppressed and overexpression of S100A10 in breast cancer PDX cells enhanced their invasion abilities and 3D organoid formation capacities in vitro. Mechanistically, S100A10 regulated the matrix metalloproteinase activity and the expression levels of stem cell–related genes. Finally, constitutive knockdown of S100A10 significantly reduced their metastatic ability to the liver in vivo. These findings suggest that S100A10 functions as a metastasis promoter of breast CSCs by conferring both invasion ability and CSC properties in breast cancers. [ABSTRACT FROM AUTHOR]

Background: Tumor budding (TB) and poorly differentiated clusters (PDCs) are a sequence of histologic findings that predict worse prognosis and node metastasis in colorectal cancer (CRC). TB and PDC (TB/PDC) are caused by cancer cell detachment and are distinguished by the number of cancer cells that constitute a cell cluster. In short, PDC is regarded as the previous step of TB. TB/PDC and epithelial-mesenchymal transition (EMT) are closely linked, but its pathogenic mechanisms are still unclear. S100A10, a member of the S100 protein family, forms a heterocomplex with annexin A2 (ANX A2) and then translocates to cell membrane from the cytoplasm and plays various roles in cell dynamics, including plasminogen activation. S100A10 is the activation modulator of the heterocomplex and promotes cell invasion. S100A10 is involved in the remodeling of both actin and extracellular matrix (ECM), which is also associated with EMT. Case presentation: In two representative cases of conventional advanced CRC, we immunohistochemically examined S100A10 and ANX A2 expressions in which both TB and PDC were prominent. Both CRCs metastasized to multiple regional lymph nodes. In both cases, a membranous positivity for S100A10 was diffusely found in both tumor buds and PDCs and was observed in the tumor cells protruding toward the stroma, giving rise to TB/PDC. However, even in tumor glands with TB/PDC, the tumor cells with a smooth border around the stroma showed either cytoplasmic fine-granular expression or no positivity. The immunoreactivity for ANX A2 was almost the same as that for S100A10. In the main tumor components without TB/PDC, no distinct positivity was detected at their smooth borders. Conclusions: During oncogenesis, membranous S100A10 has the potential to be related to TB of CRC. This may be due to plasminogen activation, actin remodeling, and interaction with an altered ECM. However, further study is required to confirm this hypothesis. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the deadliest cancers. Multiple long non‐coding RNAs (lncRNAs) are recently identified as crucial oncogenic factors or tumour suppressors. In this study, we explored the effects of LINC00174 on the progression of HCC. Expression levels of LINC00174 and microRNA‐320 (miR‐320) in HCC tissue samples were measured using quantitative real‐time polymerase chain reaction (qRT‐PCR). The association between pathological indices and LINC00174 was also analysed. Human HCC cell lines Hep3B and Huh7 were used as cell models. CCK‐8 and bromodeoxyuridine (BrdU) assays were used to assess the effect of LINC00174 on HCC cell line proliferation. Flow cytometry was used to study the effect of LINC00174 on HCC apoptosis. Transwell assay was conducted to detect the effect of LINC00174 on migration and invasion. Furthermore, luciferase reporter assay and RNA immunoprecipitation (RIP) assay were used to confirm the binding relationship between miR‐320 and LINC00174. Additionally, western blot was used to detect the regulatory function of LINC00174 on oncogene S100 calcium binding protein A10 (S100A10). We demonstrated that LINC00174 expression in HCC clinical samples was significantly increased and this was correlated with higher T stage. Its overexpression remarkably accelerated proliferation and metastasis of HCC cells while reduced apoptosis. Accordingly, knockdown of it suppressed the malignant phenotypes of HCC cells. Overexpression of LINC00174 significantly reduced the expression of miR‐320 by sponging it, in turn enhanced the expression of S100A10. In conclusion, LINC00174 is a sponge of tumour suppressor miR‐320, enhances the expression of S100A10 indirectly and functions as an oncogenic lncRNA in HCC. Significance of the study: LINC00174 is a novel lncRNA, whose function is rarely investigated. It is reported that it is oncogenic in colorectal cancer, while its role in HCC remains unclear. Herein, we report that LINC00174 is significantly up‐regulated in HCC tissues and promotes the malignant phenotypes. We demonstrate that LINC00174 functions as a sponge for miR‐320, increases the expression level of oncogene S100A10 in HCC. This study helps clarify the mechanism of HCC tumorigenesis and progression, and uncover the role of LINC00174 in human disease. [ABSTRACT FROM AUTHOR]

Mutualistic symbiosis refers to the symbiotic relationship between individuals of different species in which both individuals benefit from the association. S100A10, a member of the S100 family of Ca2+-binding proteins, exists as a tight dimer and binds two annexin A2 molecules. This association forms the annexin A2/S100A10 complex known as AIIt, and modifies the distinct functions of both proteins. Annexin A2 is a Ca2+-binding protein that binds F-actin, phospholipid, RNA, and specific polysaccharides such as heparin. S100A10 does not bind Ca2+, but binds tPA, plasminogen, certain plasma membrane ion channels, neurotransmitter receptors, and the structural scaffold protein, AHNAK. S100A10 relies on annexin A2 for its intracellular survival: in the absence of annexin A2, it is rapidly destroyed by ubiquitin-dependent and independent proteasomal degradation. Annexin A2 requires S100A10 to increase its affinity for Ca2+, facilitating its participation in Ca2+-dependent processes such as membrane binding. S100A10 binds tissue plasminogen activator and plasminogen, and promotes plasminogen activation to plasmin, which is a process stimulated by annexin A2. In contrast, annexin A2 acts as a plasmin reductase and facilitates the autoproteolytic destruction of plasmin. This review examines the relationship between annexin A2 and S100A10, and how their mutualistic symbiosis affects the function of both proteins.

The generation of the serine protease plasmin is initiated by the binding of its zymogenic precursor, plasminogen, to cell surface receptors. The proteolytic activity of plasmin, generated at the cell surface, plays a crucial role in several physiological processes, including fibrinolysis, angiogenesis, wound healing, and the invasion of cells through both the basement membrane and extracellular matrix. The seminal observation by Albert Fischer that cancer cells, but not normal cells in culture, produce large amounts of plasmin formed the basis of current-day observations that plasmin generation can be hijacked by cancer cells to allow tumor development, progression, and metastasis. Thus, the cell surface plasminogen-binding receptor proteins are critical to generating plasmin proteolytic activity at the cell surface. This review focuses on one of the twelve well-described plasminogen receptors, S100A10, which, when in complex with its regulatory partner, annexin A2 (ANXA2), forms the ANXA2/S100A10 heterotetrameric complex referred to as AIIt. We present the theme that AIIt is the quintessential cellular plasminogen receptor since it regulates the formation and the destruction of plasmin. We also introduce the term oncogenic plasminogen receptor to define those plasminogen receptors directly activated during cancer progression. We then discuss the research establishing AIIt as an oncogenic plasminogen receptor-regulated during EMT and activated by oncogenes such as SRC, RAS, HIF1α, and PML-RAR and epigenetically by DNA methylation. We further discuss the evidence derived from animal models supporting the role of S100A10 in tumor progression and oncogenesis. Lastly, we describe the potential of S100A10 as a biomarker for cancer diagnosis and prognosis.

p11 (S100A10, annexin II light chain, calpactin I light chain) is a multifunctional protein that forms a heterotetrameric complex with Annexin A2, particularly at cell membranes. p11, alone or together with Annexin A2, interacts with several ion channels and receptors and regulates their cellular localization and function. Altered levels of p11 are implicated in the pathophysiology of several forms of cancer, psychiatric disorders, and neurodegeneration. Via interactions with ion channels and receptors, p11 modulates therapeutic actions of drugs targeting brain disorders. By serving as a plasminogen receptor, p11 plays an important role in plasmin generation, fibrinolysis, angiogenesis, tumor progression, and metastasis. Here, we review mechanisms whereby p11 regulates functions of ion channels and receptors in health and disease states. The level of p11 is altered in psychiatric and neurological disorders and in various forms of cancer. Via multiple interactions with annexin A2, ion channels, and receptors, p11 is implicated in the pathophysiology of several disease states, but also in mediating therapeutic drug responses. p11 stands out as a versatile modulator of ion channels and receptors as it interacts with several distinct ion channels and receptors via a range of different mechanisms. p11 is critical for the generation of plasmin from plasminogen, which regulates fibrinolysis, angiogenesis, and tumor progression. Identification of interfaces in interactions between p11, annexin A2, and ion channels or receptors that provide pharmacophores may offer novel therapeutic targets against neurological disorders and several forms of cancer. [ABSTRACT FROM AUTHOR]

S100A10 promotes tumor invasion in various cancers. Although genetic studies on S100A10 in breast carcinoma (BC) have been used for molecular biological classification, immunohistochemical studies are lacking. We aimed to identify the correlation between S100A10 expression in BC and various pathological parameters, including morphological features to determine histological grade (HG). Immunostained serial paraffin-embedded tissue sections from 176 cases of resected BC or normal mammary ducts (controls) were assessed for the membrane expression of S100A10. Of the 176 cases, 125 conventional infiltrating ductal carcinomas were chosen, comprising 67 (53.6%) S100A10-positive tumors, whereas normal mammary ducts were S100A10-negative. S100A10 immunoreactivity in ductal carcinoma in situ (n = 51) was similar to that of invasive carcinoma. The distinct membrane-immunopositivity was correlated with high HG, severe nuclear pleomorphism, frequent mitotic counts, high Ki-67 labeling index, HER2/neu overexpression, and low estrogen receptor status (P < 0.05), but not with tubular formation, pT categories, node metastasis, vessel permeation, and pStage. Membrane overexpression of S100A10 in BC correlates with the high-grade morphological and molecular status of the carcinoma cell rather than stromal invasion and architectural deviation. Evidence points to the use of S100A10 as a biomarker representing a high-grade cellular status of BC. [ABSTRACT FROM AUTHOR]

The S100 group of calcium binding proteins is composed of 21 members that exhibit tissue/cell specific expressions. These S100 proteins bind a diverse range of targets and regulate multiple cellular processes, including proliferation, migration and differentiation. S100A10, also known as p11, binds mainly to annexin A2 and mediates the conversion of plasminogen to an active protease, plasmin. Higher S100A10 expression has been reported to link to worse outcome and/or chemoresistance in a number of cancer types in lung, breast, ovary, pancreas, gall bladder and colorectum and leukemia although some discrepancy was reported. In this review, we focused on the roles of the S100A10 in cancer. We summarized its biological functions, role in cancer progression, prognostic value and targeting of S100A10 for cancer therapy. [ABSTRACT FROM AUTHOR]

S100A10, a member of the S100 family of Ca2+-binding proteins, is a widely distributed protein involved in many cellular and extracellular processes. The best recognized role of S100A10 is the regulation, via interaction with annexin A2, of plasminogen conversion to plasmin. Plasmin, together with other proteases, induces degradation of the extracellular matrix (ECM), which is an important step in tumor progression. Additionally, S100A10 interacts with 5-hydroxytryptamine 1B (5-HT1B) receptor, which influences neurotransmitter binding and, through that, depressive symptoms. Taking this into account, it is evident that S100A10 expression in the cell should be under strict control. In this work, we summarize available literature data concerning the physiological stimuli and transcription factors that influence S100A10 expression. We also present our original results showing for the first time regulation of S100A10 expression by grainyhead-like 2 transcription factor (GRHL2). By applying in silico analysis, we have found two highly conserved GRHL2 binding sites in the 1st intron of the gene encoding S100A10 protein. Using chromatin immunoprecipitation (ChIP) and luciferase assays, we have shown that GRHL2 directly binds to these sites and that this DNA region can affect transcription of S100A10.

The tumor microenvironment (TME) is now being widely accepted as the key contributor to a range of processes involved in cancer progression from tumor growth to metastasis and chemoresistance. The extracellular matrix (ECM) and the proteases that mediate the remodeling of the ECM form an integral part of the TME. Plasmin is a broad-spectrum, highly potent, serine protease whose activation from its precursor plasminogen is tightly regulated by the activators (uPA, uPAR, and tPA), the inhibitors (PAI-1, PAI-2), and plasminogen receptors. Collectively, this system is called the plasminogen activation system. The expression of the components of the plasminogen activation system by malignant cells and the surrounding stromal cells modulates the TME resulting in sustained cancer progression signals. In this review, we provide a detailed discussion of the roles of plasminogen activation system in tumor growth, invasion, metastasis, and chemoresistance with specific emphasis on their role in the TME. We particularly review the recent highlights of the plasminogen receptor S100A10 (p11), which is a pivotal component of the plasminogen activation system.

Annexin A2 is a Ca 2+ regulated protein belonging to the Annexin family and is found in the cytoplasm and cell membrane. It can exist in a monomeric form or in a heterotetrameric form with the S100A10 dimer. The research on Annexin A2 in tumours is currently active, and studies on its role in pathogen infection are increasing. Annexin A2 plays a crucial role in the life cycle of viruses by mediating adhesion, internalization, uncoating, transport, and release. In the case of parasites, bacteria, mycoplasma, fungi, and other pathogens, Annexin A2 binds to the ligand on the pathogen, which mediates the pathogen's adhesion to the host cell, ultimately leading to infection and damage to the host. Furthermore, some studies have developed biological or chemical drugs that target Annexin A2, which have demonstrated promising anti-infective effects. Thus, targeting Annexin A2 may present a promising therapeutic approach for the treatment of diverse infectious diseases. In summary, this paper provides an overview of Annexin A2 and its role in various pathogens. It highlights its regulation of pathogen infection and its potential as a therapeutic target for the treatment of infectious diseases.

In various epithelial tissues, the epithelial monolayer acts as a barrier. To fulfill its function, the structural integrity of the epithelium is tightly controlled. When normal epithelial cells detach from the basal substratum and delaminate into the apical lumen, the apically extruded cells undergo apoptosis, which is termed anoikis. In contrast, transformed cells often become resistant to anoikis and able to survive and grow in the apical luminal space, leading to the formation of multilayered structures, which can be observed at the early stage of carcinogenesis. However, the underlying molecular mechanisms still remain elusive. In this study, we first demonstrate that S100A10 and ANXA2 (Annexin A2) accumulate in apically extruded, transformed cells in both various cell culture systems and murine epithelial tissues in vivo. ANXA2 acts upstream of S100A10 accumulation. Knockdown of ANXA2 promotes apoptosis of apically extruded RasV12-transformed cells and suppresses the formation of multilayered epithelia. In addition, the intracellular reactive oxygen species (ROS) are elevated in apically extruded RasV12 cells. Treatment with ROS scavenger Trolox reduces the occurrence of apoptosis of apically extruded ANXA2-knockdown RasV12 cells and restores the formation of multilayered epithelia. Furthermore, ROS-mediated p38MAPK activation is observed in apically delaminated RasV12 cells, and ANXA2 knockdown further enhances the p38MAPK activity. Moreover, the p38MAPK inhibitor promotes the formation of multilayered epithelia of ANXA2-knockdown RasV12 cells. These results indicate that accumulated ANXA2 diminishes the ROS-mediated p38MAPK activation in apically extruded transformed cells, thereby blocking the induction of apoptosis. Hence, ANXA2 can be a potential therapeutic target to prevent multilayered, precancerous lesions.

Annexin A2 (ANXA2), an endothelial cell receptor for plasminogen and tissue plasminogen activator, has been identified as a new autoantigen in antiphospholipid syndrome (APS). ANXA2 can exist as a monomer or a heterotetrameric complex with S100A10 protein. This S100A10 subunit also plays a pivotal role in the regulation of fibrinolysis. The aim of this study was to evaluate the prevalence of autoantibodies directed against S100A10 protein in patients with APS. Patients with primary antiphospholipid syndrome (PAPS), patients with systemic lupus erythematosus (SLE) and patients with unexplained thrombosis were retrospectively included in this study. Patients were followed in the department of Internal Medicine of Amiens University Hospital, Amiens, France. IgG and IgM anti-S100A10 antibodies were detected in the serum of patients by enzyme-linked immunosorbent assay. The cut-off value for positivity was defined as 3 standard deviations above the mean optical density (OD) obtained in the sera of 116 healthy blood donors. The study group consisted of 116 healthy individuals and 106 patients: 42 APS patients (26 patients with PAPS and 16 patients with secondary SLE-related APS), 43 SLE patients without APS and 21 patients with unexplained thrombosis. The median age of APS patients, SLE patients without APS, patients with unexplained thrombosis and healthy individuals was 47, 38, 53 and 42 years, respectively. Anti-S100A10 antibodies were detected in 11.9% of APS patients and this prevalence was statistically higher than that observed in healthy individuals (1.7%) (p = 0.0148). Highest levels of anti-S100A10 were observed in the serum of one PAPS patient with venous thrombosis and one SLE patient with APS with a history of stroke and recurrent miscarriage. S100A10 protein, the binding partner of ANXA2, was identified as a target of autoantibodies in sera from patients with APS. Further studies involving a large cohort of APS patients are required to determine whether these antibodies could play a role in thrombogenic mechanisms of APS and to determine their diagnostic value in discriminating clinical subgroups of patients with APS, particularly those with seronegative APS. • S100A10 is a binding partner of annexin A2 • S100A10 plays a pivotal role in regulation of fibrinolysis • S10010 has been identified as a new autoantigen in antiphospholipid syndrome • The prevalence of anti-S100A10 in APS patients (11.9%) was statistically higher than in control group (1.7%) • Further studies in large cohort of APS patients are needed to determine whether these antibodies could be pathogenic [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text Objective: To determine the characteristics of trauma patients with low levels of fibrinolysis as detected by viscoelastic hemostatic assay (VHA) and explore the underlying mechanisms of this subtype. Background: Hyperfibrinolysis is a central component of acute traumatic coagulopathy but a group of patients present with low levels of VHA-detected fibrinolysis. There is concern that these patients may be at risk of thrombosis if empirically administered an antifibrinolytic agent. Methods: A prospective multicenter observational cohort study was conducted at 5 European major trauma centers. Blood was drawn on arrival, within 2 hours of injury, for VHA (rotation thromboelastometry [ROTEM]) and fibrinolysis plasma protein analysis including the fibrinolytic mediator S100A10. An outcomes-based threshold for ROTEM hypofibrinolysis was determined and patients grouped by this and by D-dimer (DD) levels. Results: Nine hundred fourteen patients were included in the study. The VHA maximum lysis (ML) lower threshold was determined to be <5%. Heterogeneity existed among patients with low ML, with survivors sharing similar clinical and injury characteristics to patients with normal ML values (5–15%). Those who died were critically injured with a preponderance of traumatic brain injury and had a 7-fold higher DD level (died vs. survived: 103,170 vs. 13,672 ng/mL, P < 0.001). Patients with low ML and high DD demonstrated a hyperfibrinolytic biomarker profile, low tissue plasminogen activator levels but high plasma levels of S100A10. S100A10 was negatively correlated with %ML (r = −0.26, P < 0.001) and caused a significant reduction in %ML when added to whole blood ex-vivo. Conclusions: Patients presenting with low ML and low DD levels have low injury severity and normal outcomes. Conversely, patients with low ML but high DD levels are severely injured, functionally coagulopathic and have poor clinical outcomes. These patients have low tissue plasminogen activator levels and are not detectable by ROTEM. S100A10 is a cell surface plasminogen receptor which may drive the hyperfibrinolysis in these patients and which when shed artificially lowers %ML ex-vivo. [ABSTRACT FROM AUTHOR]

S100A10, a member of the S100 protein family, commonly forms a heterotetrameric complex with Annexin A2. This is essential for the generation of cellular plasmin from plasminogen, which leads to a cascade of molecular events crucial for tumor progression. S100A10 upregulation has been reported in a number of cancers, suggesting that it may have potential as a prognostic biomarker, as well as predicting sensitivity to anticancer drugs. This review evaluates the direct and indirect relationships between S100A10 and cancer progression by investigating its role in cancer. Research papers published on PubMed and Google Scholar between 2007–2017 were collated and reviewed. We concluded that S100A10 affects the development of the hallmarks of cancer as explained by Hanahan and Weinberg in 2011, most notably by activating the invasion and metastasis of cancer cells. However, further studies are required to explore the underlying biological mechanisms of S100A10. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is a malignancy of the lining of the stomach and is prone to distant metastasis, which involves a variety of complex molecules. The S100 proteins are a family of calcium‐binding cytosolic proteins that possess a wide range of intracellular and extracellular functions and play pivotal roles in the invasion and migration of tumour cells. Among these, S100A10 is known to be overexpressed in GC. Lysine succinylation, a recently identified form of protein post‐translational modification, is an important regulator of cellular processes. Here, we demonstrated that S100A10 was succinylated at lysine residue 47 (K47), and levels of succinylated S100A10 were increased in human GC. Moreover, K47 succinylation of S100A10 was stabilized by suppression of ubiquitylation and subsequent proteasomal degradation. Furthermore, carnitine palmitoyltransferase 1A (CPT1A) was found to function as a lysine succinyltransferase that interacts with S100A10. Succinylation of S100A10 is regulated by CPT1A, while desuccinylation is regulated by SIRT5. Overexpression of a succinylation mimetic mutant, K47E S100A10, increased cell invasion and migration. Taken together, this study reveals a novel mechanism of S100A10 accumulation mediated by succinylation in GC, which promotes GC progression and is regulated by the succinyltransferase CPT1A and SIRT5‐mediated desuccinylation. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is arguably the deadliest cancer type. The efficacy of current therapies is often hindered by the inability to predict patient outcome. As such, the development of tools for early detection and risk prediction is key for improving outcome and quality of life. Here, we introduce the plasminogen receptor S100A10 as a novel predictive biomarker and a driver of pancreatic tumor growth and invasion. We demonstrated that S100A10 mRNA and protein are overexpressed in human pancreatic tumors compared to normal ducts and nonductal stroma. S100A10 mRNA and methylation status were predictive of overall survival and recurrence‐free survival across multiple patient cohorts. S100A10 expression was driven by promoter methylation and the oncogene KRAS. S100A10 knockdown reduced surface plasminogen activation, invasiveness, and in vivo growth of pancreatic cancer cell lines. These findings delineate the clinical and functional contribution of S100A10 as a biomarker in pancreatic cancer. In this study, we perform a robust clinical and functional assessment of the plasminogen receptor S100A10 as a novel biomarker in pancreatic ductal adenocarcinoma patients. We demonstrated that S100A10 is overexpressed in pancreatic tumors and is modulated by oncogenic KRAS and DNA methylation. S100A10 also mediated in vivo tumor growth, plasminogen activation and invasion of pancreatic cancer cells. [ABSTRACT FROM AUTHOR]