Supplementary material Gut

SUPPLEMENTARY FIGURES LEGENDS

Figure S1. (A) Ontology enrichment analysis of biological processes in which selected TS/ONC identified by proteomic analysis are involved. Inter-connections between biological processes and involved are represented in B.

Figure S2. mRNA expression of TSs/ONCs in constitutive hepatocytes-specific PTEN knockout mice. (A) qRT-PCR analyses of TS/ONC in liver tissues (4 controls and 5 LPTENKO mice) from 4-months-old control and constitutive hepatocyte-specific PTEN knockout (LPTENKO) mice. Cyclophilin-A was used to normalize qRT-PCR analyses. Data represent the mean+/-SD. (B) The mRNA level of TS/ONCO candidates identified in the proteomic analysis were investigated in a transcriptomic dataset from the Omnibus Database (GSE70681, LPTENKO 3-months old. For each candidate, Log2-Fold Change between Control and LPTENKO mice were calculated and represented in a heatmap. ***P<0.001, **P<0.01, and *P<0.05 (t-test).

Figure S3. Hepatic steatosis and AKT phosphorylation in inducible hepatocytes-specific PTEN knockout mice (LIPTENKO). A. Hematoxylin/Eosin (H&E) staining of histological sections from 5-month old control and LIPTENKO mice treated with tamoxifen for 3 months.

The level of PTEN, pAKTser473, pAKTthr308 and AKT were analyzed by Western Blot (B). Corresponding quantifications are reported in C. Data represent the mean +/- SD. *P<0.05, **P<0.01, ***P<0.001 compared with controls (t-test).

Figure S4. Hepatic steatosis in ob/ob and db/db mice and analysis of TS/ONC mRNA expression in ob/ob mice. (A) Hematoxylin/Eosin (H&E) staining of histological sections from 2-month old Control, ob/ob and db/db (n=5-6 mice/group) mice. (B) A transcriptomic datasets from the GEO database was used to assess the relative mRNA levels of TS/ONC candidates in control vs ob/ob mice. For each candidate, Log2-Fold Change between Control and ob/ob mice were calculated and represented in a heatmap. *P<0.05, **P<0.01, ***P<0.001 compared with controls (t-test).

Figure S5. S100a11, Anxa2 and Lgals1 mRNA expression in steatotic livers of aged mice. (A) Hematoxylin/Eosin (H&E) staining of histological sections from 3-months (n=4) and 1- year old mice (n=9). mRNA expression levels of S100a11, Anxa2 and Lgals1 were assessed by qRT-PCR. (B) Data represent the mean +/- SD. *P<0.05, **P<0.01, ***P<0.001 compared with controls (t-test).

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Figure S6. Anxa2 and Lgals1 mRNA expression in mice fed a high-fat-containing diet (HFD) and exercising. (A) Control mice were fed a HFD for 10 weeks and subjected or not to treadmill exercise for the last 4 weeks of the HFD (PMID: 30138163). (B) Relative mRNA levels of S100a11, Anxa2 and Lgals1 were investigated by qRT-PCR analyses. Data represent the mean+/- SD (Control: n=6: mice fed a HFD: n=3; mice +HFD/exercise: n=3). *P<0.05, **P<0.01, ***P<0.001 compared with controls (One-way ANOVA).

Figure S7. Analysis of TS/ONC mRNA expression in different mice models of NAFLD. Transcriptomic datasets (see Table S3) from the GEO database were used to assess the relative mRNA levels (Fold Change) of TS/ONC candidates (S100a11, Anxa2, Lgals1, Mgll, Fasn, Acaca, Cd36 and Entpd5) between mice having hepatic steatosis (A, GSE57425, GSE38856, GSE53131 and GSE1432: mice fed a High-Fat Diet, HFD) or NASH (B, GSE63027: GNMTKO and MAT1AKO mice, GSE55747: CCL4-treated mice) and their related controls. Dashed lines indicate the 0.66 and 1.5 Fold Change limits. Data represent the mean +/- SD. *P<0.05, **P<0.01, ***P<0.001 compared with controls (t-test).

Figure S8. Summary of TSs/ONCs mRNA alterations in human/mouse transcriptomic datasets: the table summarizes the data from Figure 2C-D and Figure S7).

Figure S9. S100a11, Anxa2 and Lgals1 mRNA expression in mice mice fed a methionine/choline-deficient diet (MCD) or in Huh-7 cells treated with inflammatory cytokines. (A) Representative trichrome Masson staining of liver sections and mRNA expression of markers of inflammation/fibrosis in C57BL6/J mice were fed a standard (n=4) or MCD diet (n=6) for 2 weeks (B) Relative mRNA expression of S100a11, Anxa2 and Lgals1 in mice fed a control or MCD diet for 2 weeks. (C and D) Relative mRNA expression of S100A11 in Huh-7 or differentiated HepaRG cells treated with pro-inflammatory cytokines. Cyclophilin-A was used to normalize qRT-PCR analyses. Data represent the mean +/- SD (n=3). *P<0.05, **P<0.01, ***P<0.001 compared with controls (t-test).

Figure S10. Expression of pro-inflammatory cytokines in hepatic tumoral tissues of LPTENKO mice. qRT-PCR analyses of S100a11, Anxa2 and Lgals1 in hepatic tumoral tissues from 15-months-old control (4 mice) and tumors from LPTENKO mice (10 LPTENKO mice). Cyclophilin-A was used to normalize qRT-PCR analyses. Data represent the mean+/-SD. ***P<0.001, **P<0.01, and *P<0.05 (t-test).

Figure 11. S100A11 and ANXA2 expressions are upregulated in HCC from LPTENKO mice. (A) Anatomy of explanted livers with tumors in 1 year- and 15-months old LPTENKO

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mice and representative histologies (H&E staining) of hepatic tissues showing the presence of steatotic nodules, hepatocellular (HCC) and intrahepatic cholangiocarcinoma (ICC) in the liver of 15-months old LPTENKO mice (B) Representative Western blot and protein/mRNA quantifications of S100A11/ANXA2 expression in control hepatic tissues and HCC tumors from 15-months old LPTENKO mice (n=5 controls and 8 liver tumors from 8 different LPTENKO mice). (C) The relative mRNA level of S100a11 (Fold Change) in liver tissues of controls and LPTENKO mice were compared at the age of 4 months (presence of steatosis), 8 months (presence of steatosis and inflammation), 12 months (presence of steatotic nodules, hepatocellular adenoma and hepatocellular carcinoma) and 15 months (presence of hepatocellular carcinoma and intrahepatic cholangiocarcinoma) (this study and Horie et al, JCI, 2004). Data represent the mean+/- SD (4-months: n=4: 8-months old: n=4; 12-months-old: n=6; 15-months-old: n=10). *P<0.05, **P<0.01, ***P<0.001 compared with controls (One-way ANOVA).

Figure S12. S100A11, ANXA2 and LGALS1 expressions are upregulated in primary hepatocytes from LPTENKO mice. qRT-PCR analyses of S100a11, Anxa2 and Lgals1 in isolated primary hepatocytes from 4-months-old control and LPTENKO mice (4 controls and 4 LPTENKO mice). Cyclophilin-A was used to normalize qRT-PCR analyses. Data represent the mean+/-SD. ***P<0.001, **P<0.01, and *P<0.05 (t-test).

Figure 13. Deregulated signaling pathways in HCC and hallmarks of cancer associated with candidate TSs/ONCs identified in this study. (A) Number of potential interactions of TSs/ONCs regulating specific pathway (enrichment analysis based on Figure 3D). (B) Classification of TSs/ONCs candidates within typical hallmarks of cancer.

Figure S14. Liver tumors development in DEN-treated wild type mice. (A). Anatomy of 11 months old wild type mice injected at15 days of age with a single dose of DEN (25mg/kg) (left panel). The right panel shows representative histologies (H&E staining) of hepatic tissues showing the presence of HCC. (B) A transcriptomic dataset (GSE50431) from the GEO database was used to assess the relative mRNA levels (Fold Change) of S100a11, Anxa2 and Lgals1 in cancerous hepatocytes isolated from control or HCC from DEN-treated mice. Data represent the mean+/- SD. *P<0.05, **P<0.01, ***P<0.001 compared with controls (t-test).

Figure S15. mRNA levels of S100 family members in liver tissues from LPTENKO mice. Relative mRNA expression of family members in hepatic tissues of 3- and 15- months-old Control and LPTENKO mice. Data are derived from GEO datasets GSE70681

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and are represented as LOG2 Fold Change between control and LPTENKO mice (n=5 for the 3-months old group and n=4 for the 15-months old group) in a heatmap.

Figure S16. Expression of S100a11/Lgals1/Anxa2 and proliferation/ markers in hepatic tissues of 48h DEN-treated mice having or not in vivo silencing of S100A11. C57BL6/J mice were treated with DEN (100mg/kg) or NaCl 0.9%, sacrificed 48h after (A) and relative mRNA levels of S100a11, Lgals1 and Anxa2 were assessed by qRT-PCR (B). In panel (C), control C57BL6/J mice were transduced with control AAV8 (6 mice) or shS100a11-AAV8 (5 mice) for 10 days before i.p. injection of DEN (100mg/kg). 48h after DEN injection, mice were sacrificed and relative mRNA expression of key regulators of proliferation (Ccnd1, Mki67), DNA repair (Rad51, Mpg) and apoptosis (Tp53, Bax, Fas) were analyzed by qRT-PCR. Cyclophilin-A was used as a housekeeping gene for the PCR analyses. Data represent means+/-SD. ***P<0.001, **P<0.01, and *P<0.05 (t-test).

Figure S17. S100A11 and ANXA2 are upregulated in human and mouse hepatic cancer cells. (A). mRNA expression of S100A11 and ANXA2 in human primary hepatocytes (HPH) and human hepatic cultured cancer cells. Cyclophilin-A was used as a housekeeping gene for the PCR analyses. Representative Western blots (B) and related quantifications (C) of S100A11 and Anxa2 protein/mRNA expression in mouse primary hepatocytes (MPH) and mouse hepatic cultured cancer cells (i.e, AML12 and Hepa1-6). Data are representative of the mean +/- SD of three independent experiments *P<0.05, **P<0.01, ***P<0.001 compared with controls (t-test).

Figure S18. S100A11 direct interactors in hepatic cancer cells. (A) Representative WB and quantifications of ANXA2, AKT, PTEN and LGALS1 in S100A11 co- immunoprecipitates. S100A11 was immunoprecipitated in Huh7 cells and selected factors (ANXA2, AKT, PTEN and LGALS1) directly interacting with S100A11 were identified by Western Blot analyses. Fold of enrichments were calculated using IgG as a control. Data are representative of the mean +/- SD of three independent experiments *P<0.05, **P<0.01, ***P<0.001 compared with controls (t-test). (B) Representative WB and quantifications of ANXA2 in S100A11 co-immunoprecipitates. S100A11-GFP was overexpressed in SNU-398- 398 cells (which do not express S100A11) by transfection with a PEGFP-C2-based plasmid encoding S100A11-GFP. S100A11 was then immunoprecipitated with S100A11 specific

antibodies following induction of oxidative stress (exposure to H2O2 1mM for 1h) in SNU- 398. Representative WBs show co-immunoprecipitation of two bands for ANXA2, with the upper band (post-transcriptionally modified ANXA2, PMIDs: 15302870, 25574848, 26644180) specifically interacting with S100A11. Fold of enrichments were calculated using

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IgG as a control are represented in the bottom panel. Data are representative of the mean +/- SD of three independent experiments. *P<0.05, **P<0.01, ***P<0.001 compared with controls (t-test).

Figure S19. S100A11 and ANXA2 are upregulated in human HCC and ICC. (A) Correlation analysis (Spearman) between S100A11 and ANXA2 mRNA levels (GEPIA database) in human HCC. (B) S100A11 and ANXA2 mRNA levels in Intrahepatic Cholangiocarcinoma (ICC) as compared to the surrounding non-tumoral tissue from transcriptomic datasets (GEO database, see Table S8). The Dot-Plot represents the fold change between tumor and non-tumoral tissue for each patient (n=171 patients from 4 different studies). The percentage of patients showing a fold change >1.5 between tumors/non-tumoral tissues is indicated in red. (C) Analysis of S100A11 protein expression in human HCC as compared to the surrounding non-tumoral tissue from a proteomic analysis (PMID: 26626371, n=19 patients). The Dot-Plot represents the fold change between tumor and non-tumoral tissue for each patient. The percentage of patients showing a fold change >1.5 between tumors/non-tumoral tissues is indicated in red. (D) Representative immunohistochemistry staining of S100A11 (antibody CAB034320) and ANXA2 (antibody CAB004311) expression in human liver tumors samples (ID of samples is indicated on top of panels). Data are extracted from the Human Protein Atlas database. The qualitative assessment of the immunoreactivity of each antibody, from 11 patients with liver tumors (HCC or ICC) and 3 normal livers is represented in the right panel (undetected, Low, Medium and High staining; evaluations provided by the Human Protein Atlas database). (E) Immunocytochemical staining of S100A11 in Huh7 and HepG2 hepatic cancer cells. (F) Representative Western blot analysis of S100A11 and ANXA2 expression in conditioned media from Huh7 cells.

Figure S20. S100A11 and ANXA2 upregulation correlate with high-grade HCC. (A) GPC3, AFP, ANXA2 and S100A11 mRNA expressions in human normal liver tissues, grade1/2 HCC and grade 3 HCC. Data are derived from a transcriptomic dataset in the GEO database (GSE36411). Statistical analyses were performed with a One-way ANOVA analysis for multiple comparisons with the normal liver tissues. *P<0.05, **P<0.01, ***P<0.001. (B) Analysis of S100A11 protein level in human HCC. Data are derived from a published proteomic analysis performed on 19 patients (PMID: 26626371). Patients were stratified according to tumoral grade and fold changes differences between tumors and matched non- tumoral tissues (Fold Change<1.5 or >1.5). (C) Correlation analysis (Spearman) between S100A11 and HNF4A mRNA expressions (upper panel) (GEPIA database). (D) Stage of HCC as a function of low versus high S100A11 and/or ANXA2 expression in human HCC (data

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derived from Human Protein Atlas and TCGA). (E) Mutation rates of TP53 and CTNNB1 in liver tissues from patients with low and high S100A11/ANXA2 expression (segregated by the Human Protein Atlas database: best-separation method, see Supplementary M&M) derived from the Tumor Cancer Gene Atlas (TCGA) database.

Figure S21. S100A11 expression and mRNA stability de-differentiated hepatocytes. (A) Time scale of the experimental procedure to isolate and culture mouse primary hepatocytes (MPH) on collagen-coated petri dishes. (B) Correlation analysis (Spearman coefficient) between the Fold change mRNA level of S100A11 and Serpina1 (alpha1-antitrypsin) during five days of MPH culture post-plating. (C) Relative S100A11 mRNA expression in undifferentiated (Ud) and differentiated (Dif) HepaRG cells. Data are derived from a transcriptomic dataset in the GEO database (GSE18269). (D) mRNA expression of S100a11 and Anxa2 during different phases of mouse liver development (embryonic and post-natal). Data are derived from a transcriptomic dataset in the GEO database (GSE65063). Data are represented as Fold change relative to the d14 embryonic phase. (E) Relative mRNA levels of HNF4A and S100A11 in HepG2 transfected with a siRNA against HNF4A and in HNF4A overexpressing Hep3B cells (adenovirus-mediated overexpression). Data are derived from two transcriptomic datasets (GSE15991 and GSE66785) in the GEO database. (F) Correlation analysis (Spearman) between S100A11 and HNF4A mRNA levels (GEPIA database) in human HCC. (G) S100A11 and Myc mRNAs expression in levels in HepG2 cells, having or not HNF4A silenced by specific siRNAs, following actinomycin D treatment (4-12h). Relative mRNA levels of S100A11 and Myc were assessed by qRT-PCR analyses. Cyclophilin-A was used as a housekeeping gene for the PCR analyses. Data represent the mean +/- SD (n=3). *P<0.05, **P<0.01, ***P<0.001 (t-test).

Figure S22. Impact of PTEN downregulation, free fatty acids and glucose on S100A11/ANXA2 in hepatic cells. (A) PTEN, S100A11 and ANXA2 protein and mRNA expression in liver tissues of Control and LIPTENKO mice (6 mice/group) treated with tamoxifen for 5 days to delete PTEN expression in hepatocytes and sacrificed 4 days post tamoxifen treatment. (B) PTEN protein silencing and AKT phosphorylation (ser473) in Huh- 7, HepG2 and HepaRG hepatic cells transfected with PTEN-specific siRNAs. (C) S100A11 and ANXA2 mRNA expressions (qRT-PCR) in Huh-7, HepG2 and HepaRG hepatic cells transfected with PTEN-specific siRNAs. (D) Representative Hoechst/Bodipy staining of steatosis induction in Huh-7 treated with glucose (4.5g/l) and free fatty acids (400µM OA/PA 3.1) (left panels). The right panel illustrates S100A11 and ANXA2 mRNA expressions (qRT- PCR) in Huh-7 treated with glucose (4.5g/l) and/or free fatty acids (400µM OA/PA 3.1). Data

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represent the mean +/- SD of three independent experiments. All PCR analyses were normalized with Cyclophilin-A. * P<0.05, **P<0.01, ***P<0.001 (t-test).

Figure S23. S100A11 siRNA efficiency in hepatic cancer cells. The efficiency of S100A11 silencing in HepG2, Hep3B, Huh7 and Hepa1-6 cells was monitored by qRT-PCR 72h post- transfection. Cyclophilin-A was used as a housekeeping gene for all PCR analyses. *P<0.05, **P<0.01, ***P<0.001 compared with controls (t-tests).

Figure S24. S100A11 silencing induces apoptosis in HepG2 and Hep3B cells S100A11 was silenced in HepG2 and Hep3B cells by transfection with specific siRNAs. Apoptosis and necrosis was then evaluated 72h post-transfection by nuclear morphology using Hoechst- 33342/propidium iodide staining. Data are representative of the mean +/- SD of at least three independent experiments *P<0.05, **P<0.01, ***P<0.001 compared with controls (t-test).

Figure S25. S100A11 overexpression in SNU-398 cells. S100A11 was overexpressed in SNU-398 cells (which do not express S100A11) by transfection with PCDNA3.1-based plasmids encoding either S100A11 or S100A11 tagged with a Flag epitope. 24h post- transfection cells were processed for Western Blot analysis of S100A11 expression.

Figure S26. S100A11 and ANXA2 expression is upregulated in highly metastatic human HCC cells. Relative mRNA expression of S100A11, ANXA2, SERPINA1, ALB and HNF4A in human HCC cells with a poor metastatic potential (Huh7) or with a high metastatic potential (MHCC97L and HCCLM3). Data are derived from a transcriptomic dataset (GSE97626) from the GEO database. *P<0.05, **P<0.01, ***P<0.001 (One-way ANOVA, comparison with Huh7 cells).

Figure S27. HNF4A is an indirect regulator of S100A11 expression. The JASPAR (A) and TF2DNA (B) databases were used to identify potential HNF4α binding site within S100A11 promoter. (C) Relative mRNA levels of potential transcription factors regulating S100A11 in HepG2 cells transfected with a siRNA against HNF4A. Data are derived from a transcriptomic dataset (GSE15991) in the GEO database. Data represent the mean +/- SD. *P<0.05, **P<0.01, ***P<0.001 compared with controls (t-test).

Figure S28. Erlotinib prevents CCL4-induced S100a11 and ANXA2 mRNA expression. mRNA expression of S100a11 (A) and Anxa2 (B) in hepatic tissues of mice treated or not with CCL4 alone or CCL4+erlotinib (2 mice/condition). Data are derived from a transcriptomic dataset (GSE27640) from the GEO database.

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Figure S29. S100a11-associated protein network. Predicted and validated interacting through different mechanisms with S100A11. Data are derived from the STRING (A, confidence score: 0.150), the BIOGRID database (B) or literature (C). In panel (A-C), potential S100A11-interacting factors known to be overexpressed in human HCC (based on literature: Table S9 and Table S10) and/or in the liver of 15-months old LPTENKO (GEO dataset GSE70681) are associated with a red arrow. S100A11-interacting factors associated with a poor prognosis (based on literature: Table S9, Table S10) are labeled with a black diamond. (D) Survival analysis in patients having a low or high PLP2 expression (S100A11- interacting factors). Patient’s data are derived from the Human Protein Atlas and TCGA database. P-Value was determined using a log rank test.

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SUPPLEMENTARY TABLES LEGENDS

Table S1. Proteomic analysis of liver tissues from 4-months old control and LPTENKO mice. A proteomic analysis of liver tissues from control and LPTEN KO mice (3 mice/group) was performed by LC-MS/MS analysis. Label-free Quantifications values are indicated for each protein identified in the soluble and pellet fractions. For further analyses, LFQ values were LOG2 transformed and used to calculate LOG2 Fold Change in the different samples. Statistical analyses were performed using a t-test on LOG2 transformed LFQ values. An adjusted P-value was calculated by the FDR (False Discovery Rate, Benjamini and Hochsberg method) * P<0.05, **P<0.01, ***P<0.001.

Table S2. Classification of ONC/TS candidates based on literature. Cancer-related candidates identified in the proteomic analysis (160 proteins) were classified as TS, ONC, ONC/TS or “others” in HCC or other cancers based on literature. All PMID references are indicated for each gene. References highlighted in red correspond to the ones used to associate candidates with oncogenic pathways and/or hallmarks of cancer (Figure 3D and Figure S13B).

Table S3. Transcriptomic datasets used for mouse and human NAFLD. The different human and mouse transcriptomic datasets (from the GEO database) used for the Figure 2C-D and the Figure S7A-B are indicated with the samples source, the stage of NAFLD (Steatosis, NASH or cirrhosis) and the transcriptomic method used.

Table S4. Potential interactions between ONC/TS candidates in humans. The potential interactions between identified candidates in Human were obtained using the STRING database. For validated interactions, the PMIDs are reported.

Table S5. S100 family members in HCC and ICC. The roles of each S100 family members in HCC/ICC development are reported with their corresponding references (PMIDs).

Table S6. Transcriptomic datasets used for mouse and human HCC/ICC. The GEO database was used to analyze the expression of S100a11 and Anxa2 in mouse (12 studies) and human hepatocellular carcinoma (7 studies selected gathering a total of 490 patients + one study with sorafenib treatment) and cholangiocarcinoma (4 studies selected gathering 171 patients). For human datasets, only studies with tumoral tissues and matched non-tumoral tissues were selected. The table indicates the GEO reference of each study, the number of patients, the transcriptomic methodology and the associated PMIDs.

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Table S7. Immunostaining results for S100A11 in Human Tissue Microarray (HCC vs matched non-tumoral tissues). An immunostaining for S100A11 was performed on two different human tissue microarrays (TMA) with HCC and matched non-tumoral liver tissue (LVC481 and LVC482). Gender, age, tumoral grade and TMN classification are indicated for each patient. A qualitative assessment of the immunoreactivity was performed (IHC score: -, unstained; + weak staining; ++ moderate staining; +++ strong staining). The localization of the protein is also indicated for each patient (Nuclear or cytoplasmic).

Table S8. Immunostaining results for S100A11 in Human Tissue Microarray (HCC with unmatched non-tumoral tissues). An immunostaining for S100A11 was performed on a human tissue microarrays with HCC (BC0316A). Gender, age, tumoral grade and TMN classification are indicated for each patient. A qualitative assessment of the immunoreactivity was performed (IHC score: -, unstained; + weak staining; ++ moderate staining; +++ strong staining). The localization of the protein is also indicated for each patient (Nuclear or cytoplasmic).

Table S9. Expression and role of potential S100A11 interactors in human HCC and liver tissues from control and LPTENKO mice (3 and 15-months old). The potential partners of S100A11 in Human, identified in the STRING database, were analyzed with (Biological processes). Next, their expressions were investigated in transcriptomic datasets from liver tissues of 3-months old and 15-months old LPTENKO mice (GSE70681, GEO database). Finally the expression and the role of these proteins in human HCC were investigated in literature. The corresponding PMIDs are reported. Candidates being upregulated in LPTENKO and/or in human HCC are indicated in red.

Table S10. S100a11 network from the BIOGRID database. The potential partners of S100A11 in Human were identified with the BIOGRID database. The table displays the official interactors symbols, the experimental approach used to determine interaction, the species and the corresponding PMIDs. Finally the expression and the role of these proteins in human HCC were investigated in literature. The corresponding PMIDs are also reported.

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