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Cited by 15Gastric Cancer Management and OutcomesFerroptosis and cancer prognosisCancer Immunotherapy and Biomarkers

Phosphoserine phosphatase as a prognostic biomarker in patients with gastric cancer and its potential association with immune cells

Open access
Huang, Ma-Yan, Liu, Xiao-Yun, Shao, Qiong, Zhang, Xu, Miao, Lei, Wu, Xiao-Yan, Xu, Yu-Xia, Wang, Fang +3 more·2022·BMC Gastroenterology
DOI 10.1186/s12876-021-02073-0PMC PMC8722028
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Abstract

Background: Because of dismal prognosis in gastric cancer, identifying relevant prognostic factors is necessary. Phosphoserine phosphatase (PSPH) exhibits different expression patterns in many cancers and has been reported to affect the prognosis of patients with cancer. In this study, we examined the prognostic role of metabolic gene PSPH in gastric cancer based on the TCGA dataset and our hospital–based cohort cases. Methods: We collected and analysed RNA-seq data of Pan-cancer and gastric cancer in the TCGA dataset and PSPH expression data obtained from immunohistochemical analysis of 243 patients with gastric cancer from Sun Yat-sen University cancer center. Further, Kaplan–Meier survival analysis and Cox analysis were used to assess the effect of PSPH on prognosis. The ESTIMATE and Cibersort algorithms were used to elucidate the relationship between PSPH and the abundance of immune cells using the TCGA dataset. Results: We observed that PSPH expression displayed considerably high in gastric cancer and it was significantly associated with inferior prognosis (P = 0.043). Surprisingly, there was a significant relationship between lower immune scores and high expression of PSPH (P < 0.05). Furthermore, patients with a low amount of immune cells exhibited poor prognosis (P = 0.046). The expression of PSPH significantly increased in activated memory CD4 T cells, resting NK cells and M0 macrophages (P = 0.037, < 0.001, and 0.005, respectively). Conclusions: This study highlighted that PSPH influences the prognosis of patients with gastric cancer, and this is associated with the infiltration of tumour immune cells, indicating that PSPH may be a new immune-related target for treating gastric cancer.

AI snapshot

Written from the paper’s full text.

TL;DR

In gastric cancer, high phosphoserine phosphatase (PSPH) expression was associated with inferior prognosis and with lower immune scores, suggesting PSPH may be an immune-related prognostic biomarker. However, PSPH was not an independent prognostic factor in multivariate analysis.

Key findings

  • High PSPH expression was associated with significantly inferior overall survival in the SYSUCC gastric cancer cohort (Kaplan–Meier P = 0.043; univariate Cox HR 1.53, 95% CI 1.01–2.34, P = 0.041), but not in multivariate Cox analysis (HR 1.30, 95% CI 0.81–2.08, P = 0.275).
  • High PSPH expression was associated with lower ESTIMATE, stromal, and immune scores (P = 0.001, < 0.001, and 0.023, respectively), and low immune score was associated with poor prognosis (P = 0.046).
  • Cibersort analysis showed PSPH expression significantly increased in activated memory CD4 T cells, resting NK cells, and M0 macrophages (P = 0.037, < 0.001, and 0.005, respectively).
  • PSPH expression correlated with Lauren classification, invasion depth, and distant metastasis (P < 0.001, P < 0.001, and P = 0.012, respectively).

Methods

  • RNA-seq data from TCGA pan-cancer and TCGA-STAD were analyzed for PSPH expression; immunohistochemistry was performed on FFPE gastric cancer tissues from Sun Yat-sen University Cancer Center collected January 2014–December 2016.
  • The clinicopathological analysis included 234 patients in Table 1, although the abstract states 243 patients.
  • Kaplan–Meier survival analysis with log-rank tests and univariate/multivariate Cox analysis assessed prognosis; ESTIMATE and Cibersort algorithms analyzed immune scores and 22 immune cell subsets; Fisher’s exact test or χ² test assessed clinicopathological correlations.

Limitations

  • The paper states no formal limitations section; the authors note that further in vitro and in vivo studies are warranted to confirm the mechanism of PSPH in inhibiting immune cells.
  • Evident from the text: the hospital cohort is retrospective and single-center, and the immune analyses are correlative TCGA-based findings rather than causal.
  • Evident from the text: PSPH was not independently associated with prognosis in multivariate analysis, and no significant overall survival difference by PSPH expression was found within pathological subtypes.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1186/s12876-021-02073-0

Cites

38 of 38 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 19 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    PSPH mRNA level is significantly higher in intestinal-type gastric cancer than in normal individuals (P = 0.001).

    “Interestingly, the mRNA level of PSPH was significantly higher in patients with intestinal-type gastric cancer than in normal individuals and patients with diffuse-type gastric cancer (Fig. 1, P = 0.001 and < 0.001, respectively).”
    Quote in the paperNot a substantial claim
  • Findingown data

    PSPH mRNA level is significantly higher in intestinal-type gastric cancer than in diffuse-type gastric cancer (P < 0.001).

    “Interestingly, the mRNA level of PSPH was significantly higher in patients with intestinal-type gastric cancer than in normal individuals and patients with diffuse-type gastric cancer (Fig. 1, P = 0.001 and < 0.001, respectively).”
    Quote in the paperNot a substantial claim
  • Findingown data

    High PSPH expression is associated with lower proportions of memory B cells and resting/activated mast cells.

    “through the Cibersort algorithm, we found that the amount of resting NK cells, activated memory CD4 T cells and M0 macrophages was high in high PSPH expression group, whereas that of memory B cells and activated or resting mast cells was low.”
    Quote in the paperSubstantial claim
  • Findingown data

    In multivariate Cox analysis, PSPH expression is not independently associated with prognosis in gastric cancer (HR 1.30, 95% CI 0.81-2.08, P = 0.275).

    “However, subsequent multivariate Cox analysis revealed that invasive depth and distant metastasis were independently associated with the prognosis in gastric cancer (Table 3).”
    • Also stated in: § High PSPH level is a possible risk factor in gastric cancer · plain
      “High | 1.53 (1.01–2.34) | 0.041 | 1.30 (0.81–2.08) | 0.275”
    Quote in the paperSubstantial claim
  • Findingown data

    Low immune score is associated with poor prognosis in gastric cancer patients (P = 0.046).

    “Moreover, low immune score was associated with poor prognosis (Fig. 5C P = 0.046), whereas no relationship was observed between ESTIMATE and stromal scores and prognosis (Fig. 5A, B).”
    Quote in the paperSubstantial claim
  • May combine two claims. 8
  • Classified as probably not a substantial claim. 10

  • May combine two claims.

    Findingown data

    In multivariate Cox analysis, invasive depth and distant metastasis are independently associated with prognosis in gastric cancer.

    “However, subsequent multivariate Cox analysis revealed that invasive depth and distant metastasis were independently associated with the prognosis in gastric cancer (Table 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    High PSPH expression is associated with higher proportions of activated memory CD4 T cells, resting NK cells, and M0 macrophages.

    “The expression of PSPH significantly increased in activated memory CD4 T cells, resting NK cells and M0 macrophages (P = 0.037, < 0.001, and 0.005, respectively).”
    • Also stated in: § Discussion · plain
      “through the Cibersort algorithm, we found that the amount of resting NK cells, activated memory CD4 T cells and M0 macrophages was high in high PSPH expression group, whereas that of memory B cells and activated or resting mast cells was low.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    High PSPH expression is associated with lower ESTIMATE, stromal, and immune scores in gastric cancer patients (P = 0.001, < 0.001, and 0.023, respectively).

    “All the scores were lower in patients with high expression of PSPH (Fig. 4A–C; P = 0.001, < 0.001 and 0.023, respectively).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    PSPH expression is significantly associated with invasive depth (P < 0.001) and distant metastasis (P = 0.012) in gastric cancer patients.

    “Additionally, we also examined the relationship between PSPH expression and the clinicopathological characteristics of patients with gastric cancer such as invasive depth and distant metastasis (Table 2, P < 0.001 and P = 0.012, respectively).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    PSPH is a promising prognostic biomarker in different cancers such as advanced colorectal cancer, thyroid cancer, and melanoma.

    “PSPH is associated with the development of various cancers and is a promising prognostic biomarker in different cancers such as advanced colorectal cancer [17], thyroid cancer [18] and melanoma [19].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [17] Sato K, Masuda T, Hu Q, Tobo T, Kidogami S, Ogawa Y, Saito T, Nambara S, Komatsu H, Hirata H, et al. Phosphoserine phosphatase is a novel prognostic biomarker on chromosome 7 in colorectal cancer. Anticancer Res. 2017;37(5):2365–71. source

      Not checked in the free run.

    • cites [18] Sun WY, Kim HM, Jung WH, Koo JS. Expression of serine/glycine metabolism-related proteins is different according to the thyroid cancer subtype. J Transl Med. 2016;14(1):168. source

      Not checked in the free run.

    • cites [19] Rawat V, Malvi P, Della Manna D, Yang ES, Bugide S, Zhang X, Gupta R, Wajapeyee N. PSPH promotes melanoma growth and metastasis by metabolic deregulation-mediated transcriptional activation of NR4A1. Oncogene. 2021;40(13):2448–62. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Patients with gastric cancer with high expression of PSPH and low immune score had poor prognosis because of a high amount of M0 macrophages and a low amount of M1 macrophages.

    “Through data analysis, we found that patients with gastric cancer with high expression of PSPH and low immune score had poor prognosis because of a high amount of M0 macrophages and a low amount of M1 macrophages, which was consistent with the previous study [38].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Cheng Y, Zhu Y, Xu J, Yang M, Chen P, Xu W, Zhao J, Geng L, Gong S. PKN2 in colon cancer cells inhibits M2 phenotype polarization of tumor-associated macrophages via regulating DUSP6-Erk1/2 pathway. Mol Cancer. 2018;17(1):13. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Serine biosynthesis is necessary for T cell expansion in acquired immune responses.

    “Noga et al. reported that serine biosynthesis is necessary for T cell expansion in acquired immune responses [32].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Ron-Harel N, Santos D, Ghergurovich JM, Sage PT, Reddy A, Lovitch SB, Dephoure N, Satterstrom FK, Sheffer M, Spinelli JB, et al. Mitochondrial biogenesis and proteome remodeling promote one-carbon metabolism for T cell activation. Cell Metab. 2016;24(1):104–17. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    PSPH-mediated serine synthesis is upregulated in cancer cells as a mechanism contributing to enhanced nucleotide and amino acid synthesis and antioxidant production, and is a potential novel therapeutic target for treating cancers.

    “It is upregulated in cancer cells as a mechanism contributing to enhanced nucleotide and amino acid synthesis with regard to cell proliferation and antioxidant production, and it is a potential novel therapeutic target for treating cancers [29–31].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [29] Maddocks OD, Berkers CR, Mason SM, Zheng L, Blyth K, Gottlieb E, Vousden KH. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature. 2013;493(7433):542–6. source

      Not checked in the free run.

    • cites [30] Diehl FF, Lewis CA, Fiske BP, Vander Heiden MG. Cellular redox state constrains serine synthesis and nucleotide production to impact cell proliferation. Nat Metab. 2019;1(9):861–7. source

      Not checked in the free run.

    • cites [31] Yang M, Vousden KH. Serine and one-carbon metabolism in cancer. Nat Rev Cancer. 2016;16(10):650–62. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Alteration of tumour immune microenvironment in gastric cancer is a pivotal strategy for predicting immunotherapeutic responses and prognosis.

    “Recent studies reported that alteration of tumour immune microenvironment in gastric cancer is a pivotal strategy for predicting the immunotherapeutic responses and prognosis, which might provide new treatment strategies for patients [26, 27].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [26] Wu T, Dai Y. Tumor microenvironment and therapeutic response. Cancer Lett. 2017;387:61–8. source

      Not checked in the free run.

    • cites [27] Zeng D, Li M, Zhou R, Zhang J, Sun H, Shi M, Bin J, Liao Y, Rao J, Liao W. Tumor microenvironment characterization in gastric cancer identifies prognostic and immunotherapeutically relevant gene signatures. Cancer Immunol Res. 2019;7(5):737–50. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    EGFR amplification in lung adenocarcinoma is associated with PSPH overexpression.

    “notably, EGFR amplification in lung adenocarcinoma which was associated with PSPH overexpression [25].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Weir BA, Woo MS, Getz G, Perner S, Ding L, Beroukhim R, Lin WM, Province MA, Kraja A, Johnson LA, et al. Characterizing the cancer genome in lung adenocarcinoma. Nature. 2007;450(7171):893–8. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    M2 macrophages are mainly conducive for angiogenesis and stimulate tumour cell metastasis, whereas M1 macrophages are tumour suppressors.

    “M2 macrophages are mainly conducive for angiogenesis and stimulate tumour cell metastasis [35]; by the contrast, M1 macrophages are the tumour suppressors as per the effects of pro-inflammatory and cytotoxic cell expression.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Genin M, Clement F, Fattaccioli A, Raes M, Michiels C. M1 and M2 macrophages derived from THP-1 cells differentially modulate the response of cancer cells to etoposide. BMC Cancer. 2015;15:577. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Patients with gastric cancer with high expression of ADAMTS12 had an unfavourable prognosis, and the content of M0 macrophages was also increased.

    “Wu et al. have recently reported that patients with gastric cancer with high expression of ADAMTS12 had an unfavourable prognosis, and interestingly, the content of M0 macrophages was also increased [36].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Hou Y, Xu Y, Wu D. ADAMTS12 acts as a tumor microenvironment related cancer promoter in gastric cancer. Sci Rep. 2021;11(1):10996. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    High-risk in patients with lung cancer was associated with significantly high levels of activated memory CD4 T cells, resting NK cells, and M0 macrophages.

    “In another study, it was demonstrated that high-risk in patients with lung cancer was associated with significantly high levels of activated memory CD4 T cells, resting NK cells and M0 macrophages [37].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Chen M, Dong H, Deng S, Zhou Y. Development and validation of a prognostic nomogram for patients with lung adenocarcinoma based on a novel 6-DNA repair-related gene signature. Am J Transl Res. 2021;13(4):1952–70.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Excessive serine management can suppress inflammatory responses by increasing glutathione synthesis.

    “On the other hand, in certain animal models, excessive serine management can suppress inflammatory responses by increasing glutathione synthesis [33].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Knudsen JG, Rorsman P. Beta cell dysfunction in type 2 diabetes: drained of energy? Cell Metab. 2019;29(1):1–2. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Autophagy phenomena is highly associated with PSPH expression in cancers.

    “Autophagy phenomena is highly associated with PSPH expression in cancers [21], implicating that PSPH expression is important in gastric cell physiology and the interaction with Helicobacter, as evident from genetic polymorphisms in the population that predispose to the disease [22].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Zhang J, Wang E, Zhang L, Zhou B. PSPH induces cell autophagy and promotes cell proliferation and invasion in the hepatocellular carcinoma cell line Huh7 via the AMPK/mTOR/ULK1 signaling pathway. Cell Biol Int. 2021;45(2):305–19. source

      Not checked in the free run.

15 of 15

  • The paper relies on this without support.

    Very little is known about the prognostic role of PSPH in patients with gastric cancer.

    “However, very little is known about the prognostic role of PSPH in patients with gastric cancer.”

  • The paper relies on this without support.

    Few clinical and prognostic biomarkers are available in gastric cancer.

    “Although a few of molecular biomarkers have been used for predicting prognosis to date [5, 6], few of clinical and prognostic biomarkers are available in gastric cancer.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The up-regulation of glycolysis and one-carbon metabolism, and increased expression of corresponding enzymes, are usually observed in various neoplasms and are associated with metastasis, resistance to therapy, and poor prognosis.

    “The up-regulation of glycolysis and one-carbon metabolism, and the increased expression of genes coding for corresponding enzymes, are usually observed in various neoplasms and are associated with metastasis, resistance to therapy, and poor prognosis.”

    From 20-Hydroxyecdysone Confers Antioxidant and Antineoplastic Properties in Human Non-Small Cell Lung Cancer Cells (2023) · cites this paper as [69]

  • High expression of genes coding for these enzymes and their transcriptional regulators is strongly associated with shortened patient survival in different types of malignancies.

    “The high expression of genes coding for all of these enzymes and their transcriptional regulators is strongly associated with a shortened patient survival in different types of malignancies [66,67,68,69,70,71,72,73,74].”

    From 20-Hydroxyecdysone Confers Antioxidant and Antineoplastic Properties in Human Non-Small Cell Lung Cancer Cells (2023) · cites this paper as [69]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Inconsistent hospital-cohort size

    Minor

    The abstract reports immunohistochemical analysis of 243 patients, while the Methods and patient tables describe a cohort of 234. The text does not account for the nine-patient difference.

1 of 1

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Authors
Huang, M.-Y., Liu, X.-Y., Shao, Q., Zhang, X., Miao, L., Wu, X.-Y., Xu, Y.-X., Wang, F., Wang, H.-Y., Zeng, L., & Deng, L.
Affiliations
  • Sun Yat-sen University Cancer Center (CN)
  • Guangzhou Women and Children Medical Center (CN)
Corresponding author
  • Zeng, Liang
  • Deng, Ling
ORCID
Venue
BMC Gastroenterology
Publisher
Springer Science and Business Media LLC
Published
2022-01-03
Volume
22
Issue
1
Pages
1-1
ISSN
1471-230X (ISSN-L)
DOI
10.1186/s12876-021-02073-0
PMC
PMC8722028
OpenAlex
W4206833649
Semantic Scholar
8b58c68522b0d2127b696609f9039eac16864402
Cited by
15
References
38
Citations by year
2025: 4 · 2024: 4 · 2023: 4 · 2022: 3
FWCI
2.42
Type
journal article
Language
en
Open access
Licence
Locations
  • BMC Gastroenterology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
the Natural Science Foundation of Guangdong Province (2020A1515010313)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Gastric Cancer Management and Outcomes
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
phosphoserine phosphatase, gastric cancer, prognostic factors, tumor immune microenvironment, immune cell infiltration, immune score, CD4+ T cells, natural killer cells, M0 macrophages, metabolic genes
MeSH terms
Humans, Phosphoric Monoester Hydrolases, Prognosis, Stomach Neoplasms, Biomarkers, Tumor, Biomarkers, Kaplan-Meier Estimate

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