Expression of trefoil factor 3 is decreased in colorectal cancer

Espinoza,Ingrid; Agarwal,Sumit; Reddy,Amit; Shenoy,Veena; Subramony,Charulochana; Sakiyama,Marcelo; Fair,Logan; Poosarla,Teja; Zhou,Xinchun; Shannon Orr,W.; Lahr,Christopher; Bae,Sejong; Al Diffalha,Sameer; Manne,Upender; Gomez,Christian R.

doi:10.3892/or.2020.7829

Expression of trefoil factor 3 is decreased in colorectal cancer

Authors:
- Ingrid Espinoza
- Sumit Agarwal
- Amit Reddy
- Veena Shenoy
- Charulochana Subramony
- Marcelo Sakiyama
- Logan Fair
- Teja Poosarla
- Xinchun Zhou
- W. Shannon Orr
- Christopher Lahr
- Sejong Bae
- Sameer Al Diffalha
- Upender Manne
- Christian R. Gomez
View Affiliations

Affiliations: Department of Preventive Medicine, John D. Bower School of Population Health, University of Mississippi Medical Center, Jackson, MS 39216, USA, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA, Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39216, USA, School of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA, Department of Hematology/Oncology, University of Mississippi Medical Center, Jackson, MS 39216, USA, Department of Transplant/Hepatobiliary Surgery, University of Mississippi Medical Center, Jackson, MS 39216, USA, Department of Surgery, University of Mississippi Medical Center, Jackson, MS 39216, USA, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA, Center for Clinical and Translational Science (CCTS), University of Mississippi School of Pharmacy (UMSOP) and University of Mississippi Medical Center, Jackson, MS 39216, USA
Published online on: October 30, 2020 https://doi.org/10.3892/or.2020.7829
Pages: 254-264
Copyright: © Espinoza et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

In colorectal cancer (CRC), high expression of trefoil factor 3 (TFF3) is associated with tumor progression and reduced patient survival; however, bioinformatics analyses of public ‘omics’ databases show low TFF3 expression in CRCs as compared to normal tissues. Thus, we examined TFF3 expression in CRCs and matching normal tissues to evaluate its role in CRC progression. TFF3 gene expression was characterized using the bioinformatics portal UALCAN (http://ualcan.path.uab.edu). Tissue microarrays (TMAs) of archival CRC specimens (n=96) were immunostained with anti‑human TFF3 antibodies. Immunohistochemical (IHC) staining intensity was semi‑quantitatively scored. For this cohort, the median follow‑up was 5.4 years. Associations between clinical and pathological variables were determined using Chi‑square or Fisher's exact tests. Univariate disease‑free survival was estimated by the Kaplan‑Meier method. Omics data analyses by UALCAN showed downregulation of TFF3 expression in CRC relative to normal tissue at protein (χ2, P<0.0001) levels. There was a similar decreasing trend of TFF3 expression in the pathologic stages of the CRCs (RNA, χ2, P=0.88 and protein, χ2 P<0.0001). UALCAN data analysis showed that TFF3 exhibited 27% lower mRNA expression in tumors with mutant TP53 (P=0.007). Confirming the findings of omics analyses, IHC analysis of TMAs exhibited lower TFF3 expression in 95.6% (65 of 68) of the available normal‑tumor matching pairs (χ2, P<0.0001). There was no statistically significant association of tumor TFF3 expression with patient sex, race/ethnicity, tumor location within the colorectum, Tumor, Node, Metastasis (TNM) stage, lymph node metastasis, or surgical margins. However, low TFF3 IHC staining in tumor tissue was associated with histological grade (P=0.026). Kaplan‑Meier survival analysis showed no prognostic value of low TFF3 expression relative to those with high expression (log‑rank, P=0.605). Our findings demonstrate low expression of TFF3 in CRCs. Association between low TFF3 and histopathological features suggests involvement of this molecule in progression of CRC.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2020. CA Cancer J Clin. 70:7–30. 2020. View Article : Google Scholar
2	Thim L: A new family of growth factor-like peptides. ‘Trefoil’ disulphide loop structures as a common feature in breast cancer associated peptide (pS2), pancreatic spasmolytic polypeptide (PSP), and frog skin peptides (spasmolysins). FEBS Lett. 250:85–90. 1989. View Article : Google Scholar
3	Madsen J, Nielsen O, Tornøe I, Thim L and Holmskov U: Tissue localization of human trefoil factors 1, 2, and 3. J Histochem Cytochem. 55:505–513. 2007. View Article : Google Scholar
4	Podolsky DK, Lynch-Devaney K, Stow JL, Oates P, Murgue B, DeBeaumont M, Sands BE and Mahida YR: Identification of human intestinal trefoil factor. Goblet cell-specific expression of a peptide targeted for apical secretion. J Biol Chem. 268:6694–6702. 1993.
5	Xiao P, Ling H, Lan G, Liu J, Hu H and Yang R: Trefoil factors: Gastrointestinal-Specific proteins associated with gastric cancer. Clin Chim Acta. 450:127–134. 2015. View Article : Google Scholar
6	Taupin D and Podolsky DK: Trefoil factors: Initiators of mucosal healing. Nat Rev Mol Cell Biol. 4:721–732. 2003. View Article : Google Scholar
7	Hernandez C, Santamatilde E, McCreath KJ, Cervera AM, Diez I, Ortiz-Masia D, Martínez N, Calatayud S, Esplugues JV and Barrachina MD: Induction of trefoil factor (TFF)1, TFF2 and TFF3 by hypoxia is mediated by hypoxia inducible factor-1: Implications for gastric mucosal healing. Br J Pharmacol. 156:262–272. 2009. View Article : Google Scholar
8	Samson MH: Quantitative measurements of trefoil factor family peptides: Possibilities and pitfalls. Scand J Clin Lab Invest. 73:193–202. 2013. View Article : Google Scholar
9	Aihara E, Engevik KA and Montrose MH: Trefoil factor peptides and gastrointestinal function. Annu Rev Physiol. 79:357–380. 2017. View Article : Google Scholar
10	Wong WM, Poulsom R and Wright NA: Trefoil peptides. Gut. 44:890–895. 1999. View Article : Google Scholar
11	Babyatsky M, Lin J, Yio X, Chen A, Zhang JY, Zheng Y, Twyman C, Bao X, Schwartz M, Thung S, et al: Trefoil factor-3 expression in human colon cancer liver metastasis. Clin Exp Metastasis. 26:143–151. 2009. View Article : Google Scholar
12	Garraway IP, Seligson D, Said J, Horvath S and Reiter RE: Trefoil factor 3 is overexpressed in human prostate cancer. Prostate. 61:209–214. 2004. View Article : Google Scholar
13	Kannan N, Kang J, Kong X, Tang J, Perry JK, Mohankumar KM, Miller LD, Liu ET, Mertani HC, Zhu T, et al: Trefoil factor 3 is oncogenic and mediates anti-estrogen resistance in human mammary carcinoma. Neoplasia. 12:1041–1053. 2010. View Article : Google Scholar
14	Kirikoshi H and Katoh M: Expression of TFF1, TFF2 and TFF3 in gastric cancer. Int J Oncol. 21:655–659. 2002.
15	Kim WG, Kim JY and Park DY: Simple classifiers for molecular subtypes of colorectal cancer. Arab J Gastroenterol. 18:191–200. 2017. View Article : Google Scholar
16	Jahan R, Shah A, Kisling SG, Macha MA, Thayer S, Batra SK and Kaur S: Odyssey of trefoil factors in cancer: Diagnostic and therapeutic implications. Biochim Biophys Acta Rev Cancer. 1873:1883622020. View Article : Google Scholar
17	Yusup A, Huji B, Fang C, Wang F, Dadihan T, Wang HJ and Upur H: Expression of trefoil factors and TWIST1 in colorectal cancer and their correlation with metastatic potential and prognosis. World J Gastroenterol. 23:110–120. 2017. View Article : Google Scholar
18	Li Q, Wang K, Su C and Fang J: Serum trefoil factor 3 as a protein biomarker for the diagnosis of colorectal cancer. Technol Cancer Res Treat. 16:440–445. 2017. View Article : Google Scholar
19	Huang YG, Li YF, Wang LP and Zhang Y: Aberrant expression of trefoil factor 3 is associated with colorectal carcinoma metastasis. J Cancer Res Ther. 9:376–380. 2013. View Article : Google Scholar
20	Chandrashekar DS, Bashel B, Balasubramanya SA, Creighton CJ, Ponce-Rodriguez I, Chakravarthi B and Varambally S: UALCAN: A portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia. 19:649–658. 2017. View Article : Google Scholar
21	Chen F, Chandrashekar DS, Varambally S and Creighton CJ: Pan-Cancer molecular subtypes revealed by mass-spectrometry-based proteomic characterization of more than 500 human cancers. Nat Commun. 10:56792019. View Article : Google Scholar
22	Mashimo H, Wu DC, Podolsky DK and Fishman MC: Impaired defense of intestinal mucosa in mice lacking intestinal trefoil factor. Science. 274:262–265. 1996. View Article : Google Scholar
23	Farrell JJ, Taupin D, Koh TJ, Chen D, Zhao CM, Podolsky DK and Wang TC: TFF2/SP-deficient mice show decreased gastric proliferation, increased acid secretion, and increased susceptibility to NSAID injury. J Clin Invest. 1091:193–204. 2002. View Article : Google Scholar
24	Carrasco R, Pera M, May FE, Westley BR, Martinez A and Morales L: Trefoil factor family peptide 3 prevents the development and promotes healing of ischemia-reperfusion injury in weanling rats. J Pediatr Surg. 39:1693–1700. 2004. View Article : Google Scholar
25	Serwin NM, Wisniewska M, Jesionowska A, Skwirczyńska E, Marcinowska Z and Dołęgowska B: Serum levels of 12 renal function and injury markers in patients with glomerulonephritis. Pol Arch Med Wewn. 126:483–493. 2016.
26	Schulze U, Hampel U, Sel S, Goecke TW, Thäle V, Garreis F and Paulsen F: Fresh and cryopreserved amniotic membrane secrete the trefoil factor family peptide 3 that is well known to promote wound healing. Histochem Cell Biol. 138:243–250. 2012. View Article : Google Scholar
27	Taupin DR, Kinoshita K and Podolsky DK: Intestinal trefoil factor confers colonic epithelial resistance to apoptosis. Proc Natl Acad Sci USA. 97:799–804. 2000. View Article : Google Scholar
28	Kinoshita K, Taupin DR, Itoh H and Podolsky DK: Distinct pathways of cell migration and antiapoptotic response to epithelial injury: Structure-function analysis of human intestinal trefoil factor. Mol Cell Biol. 20:4680–4690. 2000. View Article : Google Scholar
29	Li XL, Zhou J, Chen ZR and Chng WJ: P53 mutations in colorectal cancer-molecular pathogenesis and pharmacological reactivation. World J Gastroenterol. 21:84–93. 2015. View Article : Google Scholar
30	Manne U, Myers RB, Moron C, Poczatek RB, Dillard S, Weiss H, Brown D, Srivastava S and Grizzle WE: Prognostic significance of bcl-2 expression and p53 nuclear accumulation in colorectal adenocarcinoma. Int J Cancer. 74:346–358. 1997. View Article : Google Scholar
31	Busch M, Klein S, Große-Kreul J, Scheiner O, Metz K, Stephan H and Dünker N: P53, miR-34a and EMP1-newly identified targets of TFF3 signaling in Y79 retinoblastoma cells. Int J Mol Sci. 20:41292019. View Article : Google Scholar
32	Goswami CP and Nakshatri H: PROGgeneV2: Enhancements on the existing database. BMC Cancer. 14:9702014. View Article : Google Scholar
33	Morito K, Nakamura J, Kitajima Y, Kai K, Tanaka T, Kubo H, Miyake S and Noshiro H: The value of trefoil factor 3 expression in predicting the longterm outcome and early recurrence of colorectal cancer. Int J Oncol. 46:563–568. 2015. View Article : Google Scholar
34	Scholven J, Taras D, Sharbati S, Schön J, Gabler C, Huber O, zum Büschenfelde DM, Blin N and Einspanier R: Intestinal expression of TFF and related genes during postnatal development in a piglet probiotic trial. Cell Physiol Biochem. 23:143–156. 2009. View Article : Google Scholar