Accumulation of annexin A2 and S100A10 prevents apoptosis of apically delaminated, transformed epithelial cells.

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.

Modulation of prostaglandin transport activity of SLCO2A1 by annexin A2 and S100A10.

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.

Ca2+ ions facilitate the organization of the Annexin A2/S100A10 heterotetramer.

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.

S100A family is a group of immune markers associated with poor prognosis and immune cell infiltration in hepatocellular carcinoma.

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.

Rho Kinase Inhibitor Y27632 Improves Recovery After Spinal Cord Injury by Shifting Astrocyte Phenotype and Morphology via the ROCK/NF-κB/C3 Pathway.

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.

The prognostic value of S100A calcium binding protein family members in predicting severe forms of COVID-19.

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.

S100A10 regulates tumor necrosis factor alpha-induced apoptosis in chondrocytes via the reactive oxygen species/nuclear factor-kappa B pathway.

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.

Osteopontin regulates proliferation, migration, and survival of astrocytes depending on their activation phenotype.

The glycoprotein osteopontin is highly upregulated in central nervous system (CNS) disorders such as ischemic stroke. Osteopontin regulates cell growth, cell adhesion, homeostasis, migration, and survival of various cell types. Accordingly, osteopontin is considered an essential regulator of regeneration and repair in the ischemic milieu. Astrocytes are the most abundant cells in the CNS and play significant roles in health and disease. Astrocytes are involved in homeostasis, promote neuroprotection, and regulate synaptic plasticity. Upon activation, astrocytes may adopt different phenotypes, termed A1 and A2. The direct effects of osteopontin on astrocytes, especially in distinct activation states, are yet unknown. The current study aimed to elucidate the impact of osteopontin on resting and active astrocytes. We established an inflammatory in vitro model of activated (A1) primary astrocytes derived from neonatal wistar rats by exposure to a distinct combination of proinflammatory cytokines. To model ischemic stroke in vitro, astrocytes were subjected to oxygen and glucose deprivation (OGD) in the presence or absence of osteopontin. Osteopontin modulated the activation phenotype by attenuating A1- and restoring A2-marker expression without compromising the active astrocytes' immunocompetence. Osteopontin promoted the proliferation of active and the migration of resting astrocytes. Following transient OGD, osteopontin mitigated the delayed ongoing death of primary astrocytes, promoting their survival. Data suggest that osteopontin differentially regulates essential functions of resting and active astrocytes and confirm a significant regulatory role of osteopontin in an in vitro ischemia model. Furthermore, the data suggest that osteopontin constitutes a promising target for experimental therapies modulating neuroregeneration and repair.

Upregulation of S100A10 in metastasized breast cancer stem cells.

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.

Annexin A2-S100A10 Represents the Regulatory Component of Maxi-Cl Channel Dependent on Protein Tyrosine Dephosphorylation and Intracellular Ca²âº.

BACKGROUND/AIMS: Maxi-anion channel (Maxi-Cl) is ubiquitously expressed and involved in a number of important cell functions especially by serving as an ATP release pathway. We recently identified SLCO2A1 as its essential core component. However, the regulatory component required for the channel activation/inactivation remains unidentified. METHODS: In the present study, to identify the regulatory component, we made genome-wide analysis combined with siRNA screening and performed patch-clamp studies and ATP release assay after gene silencing and overexpression. RESULTS: Comparative microarray analysis between Maxi-Cl-rich C127 and -deficient C1300 cells revealed highly differential expression not only of SLCO2A1 but also of four annexin family members. Gene silencing study showed that Anxa2 is involved in Maxi-Cl activity. The Maxi-Cl events appeared in C1300 cells by overexpression of Slco2a1 and more efficiently by that of Slco2a1 plus Anxa2. Immunoprecipitation assay supported the interaction between ANXA2 and SLCO2A1. Suppressive effects of overexpression of a phospho-mimicking mutant of Anxa2, Anxa2-Y23E, indicated that protein tyrosine dephosphorylation dependence of Maxi-Cl is conferred by ANXA2. Maxi-Cl activity was suppressed by gene silencing of S100A10, a binding partner of ANXA2, and by applying a synthetic ANXA2 peptide, Ac-(1-14), which interferes with the ANXA2-S100A10 complex formation. Intracellular Ca2+ dependence of Maxi-Cl activity was abolished by S100a10 knockdown. CONCLUSION: The ANXA2-S100A10 complex represents the regulatory component of Maxi-Cl conferring protein tyrosine dephosphorylation dependence and intracellular Ca2+ sensitivity on this channel.

LINC00174 is an oncogenic lncRNA of hepatocellular carcinoma and regulates miR-320/S100A10 axis.

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.

Membranous S100A10 involvement in the tumor budding of colorectal cancer during oncogenesis: report of two cases with immunohistochemical analysis.

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.

Alterations of p11 in brain tissue and peripheral blood leukocytes in Parkinson's disease.

Individuals with Parkinson's disease (PD) often suffer from comorbid depression. P11 (S100A10), a member of the S100 family of proteins, is expressed widely throughout the body and is involved in major depressive disorder and antidepressant response. Central p11 levels are reduced in postmortem tissue from depressed individuals; however, p11 has not yet been investigated in PD patients with depression or those without depression. We investigated p11 levels in postmortem PD brains and assessed whether peripheral p11 levels correlate with disease severity. Substantia nigra, putamen, and cortical p11 protein levels were assessed in postmortem brain samples from PD patients and matched controls. In a different set of postmortem brains, p11 mRNA expression was measured in dopaminergic cells from the substantia nigra. Both p11 protein and mRNA levels were decreased in PD patients. Peripheral p11 protein levels were investigated in distinct leukocyte populations from PD patients with depression and those without depression. Monocyte, natural killer (NK) cell, and cytotoxic T-cell p11 levels were positively associated with the severity of PD, and NK cell p11 levels were positively associated with depression scores. Given that inflammation plays a role in both PD and depression, it is intriguing that peripheral p11 levels are altered in immune cells in both conditions. Our data provide insight into the pathological alterations occurring centrally and peripherally in PD. Moreover, if replicated in other cohorts, p11 could be an easily accessible biomarker for monitoring the severity of PD, especially in the context of comorbid depression.

Membranous overexpression of S100A10 is associated with a high-grade cellular status of breast carcinoma.

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.

CPT1A-mediated succinylation of S100A10 increases human gastric cancer invasion.

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.

Multiple functions of S100A10, an important cancer promoter.

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.

p11 modulates L-DOPA therapeutic effects and dyskinesia via distinct cell types in experimental Parkinsonism.

The reduced movement repertoire of Parkinson's disease (PD) is mainly due to degeneration of nigrostriatal dopamine neurons. Restoration of dopamine transmission by levodopa (L-DOPA) relieves motor symptoms of PD but often causes disabling dyskinesias. Subchronic L-DOPA increases levels of adaptor protein p11 (S100A10) in dopaminoceptive neurons of the striatum. Using experimental mouse models of Parkinsonism, we report here that global p11 knockout (KO) mice develop fewer jaw tremors in response to tacrine. Following L-DOPA, global p11KO mice show reduced therapeutic responses on rotational motor sensitization, but also develop less dyskinetic side effects. Studies using conditional p11KO mice reveal that distinct cell populations mediate these therapeutic and side effects. Selective deletion of p11 in cholinergic acetyltransferase (ChAT) neurons reduces tacrine-induced tremor. Mice lacking p11 in dopamine D2R-containing neurons have a reduced response to L-DOPA on the therapeutic parameters, but develop dyskinetic side effects. In contrast, mice lacking p11 in dopamine D1R-containing neurons exhibit tremor and rotational responses toward L-DOPA, but develop less dyskinesia. Moreover, coadministration of rapamycin with L-DOPA counteracts L-DOPA-induced dyskinesias in wild-type mice, but not in mice lacking p11 in D1R-containing neurons. 6-OHDA lesioning causes an increase of evoked striatal glutamate release in wild type, but not in global p11KO mice, indicating that altered glutamate neurotransmission could contribute to the reduced L-DOPA responsivity. These data demonstrate that p11 located in ChAT or D2R-containing neurons is involved in regulating therapeutic actions in experimental PD, whereas p11 in D1R-containing neurons underlies the development of L-DOPA-induced dyskinesias.

S100A10 upregulation associates with poor prognosis in lung squamous cell carcinoma.

S100A10 is one of the members of the S100 protein family and is a key plasminogen receptor. Its upregulation has been reported in many types of tumors. In lung cancer, an association between upregulation of S100A10 and poor prognoses has been reported only in adenocarcinoma. We pursued the possibility of significance in lung squamous cell carcinoma (SCC). We first examined S100A10 protein expression by immunohistochemistry in 120 primary resected lung SCCs; 33 (27.5%) tumors showed strong membranous-immunopositivity particularly at the invasive front, i.e., the cancer-cell surface in contact with the stroma. Expression levels were significantly associated with higher pathological TNM stage (P = 0.0119), tumor size (P = 0.0003), lymphatic invasion (P = 0.0005), lymph node metastasis (P = 0.0006), and poorer prognosis (P = 0.0064). Our present results suggest that high S100A10 expression of the lung SCC cells, particularly adjacent to stroma, plays an important role in tumor progression, probably caused by lymphatic invasion and nodal metastasis.

S100A10 and Cancer Hallmarks: Structure, Functions, and its Emerging Role in Ovarian Cancer.

S100A10, which is also known as p11, is located in the plasma membrane and forms a heterotetramer with annexin A2. The heterotetramer, comprising of two subunits of annexin A2 and S100A10, activates the plasminogen activation pathway, which is involved in cellular repair of normal tissues. Increased expression of annexin A2 and S100A10 in cancer cells leads to increased levels of plasmin-which promotes the degradation of the extracellular matrix-increased angiogenesis, and the invasion of the surrounding organs. Although many studies have investigated the functional role of annexin A2 in cancer cells, including ovarian cancer, S100A10 has been less studied. We recently demonstrated that high stromal annexin A2 and high cytoplasmic S100A10 expression is associated with a 3.4-fold increased risk of progression and 7.9-fold risk of death in ovarian cancer patients. Other studies have linked S100A10 with multidrug resistance in ovarian cancer; however, no functional studies to date have been performed in ovarian cancer cells. This article reviews the current understanding of S100A10 function in cancer with a particular focus on ovarian cancer.

Annexin A2 and S100A10 in the mammalian oviduct.

In many mammals, upon entry into the female reproductive tract, a subpopulation of sperm is stored in the oviduct forming a functional reservoir. In the oviducts of pig and cow, Annexin A2 (AnxA2) has been linked to the binding of sperm. This protein may exist as a monomer or bound to S100A10 and both forms are associated with different biological functions. S100A10 has not yet been reported in the oviduct. The objective of this work is to analyze for the presence of S100A10 in the oviduct and to advance the study of AnxA2 and S100A10 in this organ. This work shows the presence of both proteins, AnxA2 and S100A10, in the oviduct of human, pig, cow, cat, dog and rabbit. At least in pig, AnxA2 is found devoid of S100A10 in the outer surface of the apical plasma membrane of oviductal epithelial cells, indicating that it binds to sperm as a monomer or in association with proteins different from S100A10. In the apical cytoplasm of pig oviductal epithelial cells, AnxA2 is associated with S100A10. In primary culture of porcine oviductal cells, the expression of ANXA2 is increased by progesterone, while the expression of S100A10 is increased by progesterone and estradiol. The widespread detection of both proteins in the oviduct of mammals indicates a probable conserved function in this organ. In summary, S100A10 and AnxA2 are widespread in the mammalian oviduct but AnxA2 binds sperm in vivo devoid of S100A10 and may be related to reservoir formation.