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Clinical impact of circulating LAPTM4B-35 in pancreatic ductal adenocarcinoma

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Abstract

Purpose

LAPTM4B is upregulated in a wide range of cancers associated with poor prognosis. However, the clinical impact of LAPTM4B as diagnostic and prognostic marker in pancreatic ductal adenocarcinoma (PDAC) remains unknown. Thus, the aim of the present study was to investigate the expression of LAPTM4B as circulating marker in PDAC.

Methods

Expression analysis of LAPTM4B-35 in pancreatic tissue and preoperative blood serum samples of 169 patients with PDAC UICC Stages I–IV (n = 98), chronic pancreatitis (n = 41), and healthy controls (n = 30) by immunohistochemistry, Western blot, and ELISA. Descriptive and explorative statistical analyses of LAPTM4B-35’s potential as diagnostic and prognostic marker in PDAC.

Results

Expression of LAPTM4B-35 was significantly increased in tumor tissue and corresponding blood serum samples of patients with PDAC (each p < 0.001) and it could well discriminate PDAC from healthy controls and chronic pancreatitis (p < 0.001; p = 0.0037). LAPTM4B-35 in combination with CA.19-9 outperforms the diagnostic accuracy with an AUC of 0.903 (p < 0.001), sensitivity of 82%, and specificity of 92%. Kaplan–Meier survival analysis revealed an improved overall survival in PDAC UICC I–IV with low expression of circulating LAPTM4B-35 (17 versus 10 months, p = 0.039) as well as an improved relapse-free survival in curatively treated PDAC UICC I–III (16 versus 10 months; p = 0.037). Multivariate overall and recurrence-free survival analyses identified LAPTM4B-35 as favorable prognostic factor in PDAC patients (HR 2.73, p = 0.021; HR 3.29, p = 0.003).

Conclusion

LAPTM4B-35 is significantly deregulated in PDAC with high diagnostic and prognostic impact as circulating tumor marker.

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Abbreviations

AUC:

Area under the curve

CA.19-9:

Cancer antigen 19-9

HR:

Hazard ratio

CI:

Confidence interval

IHC:

Immunohistochemistry

ELISA:

Enzyme-linked immune-sorbent assay

LAPTM4B:

Lysosome-associated protein transmembrane-4beta

PDAC:

Pancreatic ductal adenocarcinoma

ROC:

Receiver operating characteristic

SEM:

Standard error of mean

UICC:

Union internationale contre le cancer

References

  1. Amin MB et al (2017) The Eighth Edition AJCC Cancer staging manual: continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin 67:93–99. https://doi.org/10.3322/caac.21388

  2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424. https://doi.org/10.3322/caac.21492

  3. Cheng XJ et al (2015) LAPTM4B-35, a cancer-related gene, is associated with poor prognosis in TNM Stages I–III gastric cancer patients. Plos One. https://doi.org/10.1371/journal.pone.0121559

  4. Dhayat SA, Abdeen B, Kohler G, Senninger N, Haier J, Mardin WA (2015) MicroRNA-100 and microRNA-21 as markers of survival and chemotherapy response in pancreatic ductal adenocarcinoma UICC stage II. Clin Epigenet 7:132. https://doi.org/10.1186/s13148-015-0166-1

  5. Hidalgo M (2010) Pancreatic cancer. N Engl J Med 362:1605–1617. https://doi.org/10.1056/NEJMra0901557

  6. Kamisawa T, Wood LD, Itoi T, Takaori K (2016) Pancreatic cancer. Lancet 388:73–85. https://doi.org/10.1016/S0140-6736(16)00141-0

  7. Kang Y, Yin MZ, Jiang W, Zhang HY, Xia BR, Xue YW, Huang YN (2012) Overexpression of LAPTM4B-35 is associated with poor prognosis in colorectal carcinoma. Am J Surg 204:677–683. https://doi.org/10.1016/j.amjsurg.2012.02.003

  8. Kasper G et al (2005) The human LAPTM4b transcript is upregulated in various types of solid tumours and seems to play a dual functional role during tumour progression. Cancer Lett 224:93–103. https://doi.org/10.1016/j.canlet.2004.10.004

  9. Li L et al (2010) LAPTM4B: a novel cancer-associated gene motivates multidrug resistance through efflux and activating PI3K/AKT signaling. Oncogene 29:5785–5795. https://doi.org/10.1038/onc.2010.303

  10. Lim JE, Chien MW, Earle CC (2003) Prognostic factors following curative resection for pancreatic adenocarcinoma: a population-based, linked database analysis of 396 patients. Ann Surg 237:74–85. https://doi.org/10.1097/01.SLA.0000041266.10047.38

  11. Liu J, Zhou R, Zhang N, Rui J, Jin C (2000) Biological function of a novel gene overexpressed in human hepatocellular carcinoma. Chin Med J (Engl) 113:881–885

  12. Liu XR, Xiong FX, Wei XH, Yang H, Zhou RL (2009) LAPTM4B-35, a novel tetratransmembrane protein and its PPRP motif play critical roles in proliferation and metastatic potential of hepatocellular carcinoma cells. Cancer Sci 100:2335–2340. https://doi.org/10.1111/j.1349-7006.2009.01346.x

  13. Meng FL, Yin MZ, Song HT, Yang H, Lou G, Zhou RL (2010) LAPTM4B-35 overexpression is an independent prognostic marker in endometrial carcinoma. Int J Gynecol Cancer 20:745–750. https://doi.org/10.1111/IGC.0b013e3181e02f90

  14. Meng Y et al (2016) LAPTM4B: an oncogene in various solid tumors and its functions. Oncogene 35:6359–6365. https://doi.org/10.1038/onc.2016.189

  15. Neuzillet C et al (2015) State of the art and future directions of pancreatic ductal adenocarcinoma therapy. Pharmacol Ther 155:80–104. https://doi.org/10.1016/j.pharmthera.2015.08.006

  16. Qiao M, Hu GH (2015) Lysosome-associated protein transmembrane-4 beta-35 is a novel independent prognostic factor in small cell lung cancer. Tumor Biol 36:7493–7499. https://doi.org/10.1007/s13277-015-3467-2

  17. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM (2014) Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United. States Cancer Res 74:2913–2921. https://doi.org/10.1158/0008-5472.CAN-14-0155

  18. Shao GZ et al (2003) Molecular cloning and characterization of LAPTM4B, a novel gene upregulated in hepatocellular carcinoma. Oncogene 22:5060–5069. https://doi.org/10.1038/sj.onc.1206832

  19. Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA Cancer J Clin 68:7–30. https://doi.org/10.3322/caac.21442

  20. Tan XJ, Sun Y, Thapa N, Liao YH, Hedman AC, Anderson RA (2015) LAPTM4B is a PtdIns(4,5)P-2 effector that regulates EGFR signaling, lysosomal sorting, and degradation. Embo J 34:475–490. https://doi.org/10.15252/embj.201489425

  21. Vergarajauregui S, Martina JA, Puertollano R (2011) LAPTMs regulate lysosomal function and interact with mucolipin 1: new clues for understanding mucolipidosis type IV. J Cell Sci 124:459–468. https://doi.org/10.1242/jcs.076240

  22. Wang B, Wang S, Liang G, Xu J, Zhou R, Zhang Q (2017) Association of lysosomal protein transmembrane 4 beta gene polymorphism with pancreatic carcinoma susceptibility in the Chinese population. Tumour Biol 39:1010428317705518. https://doi.org/10.1177/1010428317705518

  23. Xia LZ et al (2015) The relationship between LAPTM4B polymorphisms and cancer risk in Chinese Han population: a meta-analysis. Springerplus. https://doi.org/10.1186/s40064-015-0941-7

  24. Xiao M, Jia SS, Wang HB, Wang JS, Huang YX, Li ZG (2013) Overexpression of LAPTM4B: an independent prognostic marker in breast cancer. J Cancer Res Clin 139:661–667. https://doi.org/10.1007/s00432-012-1368-y

  25. Yang H et al (2010a) LAPTM4B-35 is a novel prognostic factor of hepatocellular carcinoma. J Surg Oncol 101:363–369. https://doi.org/10.1002/jso.21489

  26. Yang H, Xiong FX, Wei XH, Yang Y, McNutt MA, Zhou RL (2010b) Overexpression of LAPTM4B-35 promotes growth and metastasis of hepatocellular carcinoma in vitro and in vivo. Cancer Lett 294:236–244. https://doi.org/10.1016/j.canlet.2010.02.006

  27. Yin MZ et al (2011) Over-expression of LAPTM4B is associated with poor prognosis and chemotherapy resistance in stages III and IV epithelial ovarian cancer. J Surg Oncol 104:29–36. https://doi.org/10.1002/jso.21912

  28. Zhang G, Liang Y, Huang Y, Chen Y, Zhou R (2012) Elevated lysosome-associated protein transmembrane-4beta-35 is an independent prognostic marker in pancreatic carcinoma. J Int Med Res 40:1275–1283. https://doi.org/10.1177/147323001204000406

  29. Zhang HT et al (2014) Overexpression of LAPTM4B-35: a novel marker of poor prognosis of prostate cancer. Plos One. https://doi.org/10.1371/journal.pone.0091069

  30. Zhang X, Shi S, Zhang B, Ni Q, Yu X, Xu J (2018) Circulating biomarkers for early diagnosis of pancreatic cancer: facts and hopes. Am J Cancer Res 8:332–353

  31. Zhou L et al (2008) Expression of LAPTM4B-35: A novel marker of progression, invasiveness and poor prognosis of extrahepatic cholanglocarcinoma. Cancer Lett 264:209–217. https://doi.org/10.1016/j.canlet.2008.01.025

  32. Zhou L, He XD, Yu JC, Zhou RL, Shan Y, Rui JA (2011) Overexpression of LAPTM4B-35 attenuates epirubucin-induced apoptosis of gallbladder carcinoma GBC-SD cells. Surgery 150:25–31. https://doi.org/10.1016/j.surg.2010.12.010

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Acknowledgements

We thank the patients and clinicians contributing to this study. Particularly, we thank Sabine von Rueden, Ludgera Weber-Koberg, Petra Ahrens, and Dr. med. Verena Raetzel (Department of General, Visceral and Transplantation Surgery, University Hospital Muenster) and Dr. med. Jan Rehkaemper (Gerhard Domagk Institute of Pathology, University Hospital Muenster) for their support and expert technical assistance. These results are part of the MD thesis of Zixuan Yang, who was supported by the China Scholarship Council (CSC).

Funding

The authors declare that they have no funding to disclose.

Author information

Conceptualization: SAD; methodology: ZY; SAD; validation: SAD; formal analysis: ZY, SAD; investigation: ZY, SAD, IF; resources: SAD, NS; writing-original draft preparation: SAD and ZY; writing-review and editing: SAD and ZY; visualization: ZY, SAD; supervision: SAD, NS, QJ; project administration: SAD; funding acquisition: NS, QJ.

Correspondence to Sameer A. Dhayat.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Yang, Z., Senninger, N., Flammang, I. et al. Clinical impact of circulating LAPTM4B-35 in pancreatic ductal adenocarcinoma. J Cancer Res Clin Oncol 145, 1165–1178 (2019). https://doi.org/10.1007/s00432-019-02863-w

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Keywords

  • Pancreatic ductal adenocarcinoma
  • Circulating LAPTM4B-35
  • Prognostic marker