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. 2021 Nov;24(6):1254-1263.
doi: 10.1007/s10120-021-01203-7. Epub 2021 Jun 11.

FHOD1 and FMNL1 formin proteins in intestinal gastric cancer: correlation with tumor-infiltrating T lymphocytes and molecular subtypes

Naziha Mansuri  1 , Vanina D Heuser  2 , Eva-Maria Birkman  3 , Minnamaija Lintunen  3 , Annika Ålgars  4 , Jari Sundström  3 , Raija Ristamäki  4 , Olli Carpén  2   5 , Laura Lehtinen  2
Affiliations

FHOD1 and FMNL1 formin proteins in intestinal gastric cancer: correlation with tumor-infiltrating T lymphocytes and molecular subtypes

Naziha Mansuri et al. Gastric Cancer. 2021 Nov.

Abstract

Background: Gastric cancer (GC) is the third most common cause of cancer death. Intestinal type GC is a molecularly diverse disease. Formins control cytoskeletal processes and have been implicated in the progression of many cancers. Their clinical significance in GC remains unclear. Here, we characterize the expression of formin proteins FHOD1 and FMNL1 in intestinal GC tissue samples and investigate their association with clinical parameters, GC molecular subtypes and intratumoral T lymphocytes.

Methods: The prognostic significance of FHOD1 and FMNL1 mRNA expression was studied with Kaplan-Meier analyses in an online database. The expression of FHOD1 and FMNL1 proteins was characterized in GC cells, and in non-neoplastic and malignant tissues utilizing tumor microarrays of intestinal GC representing different molecular subtypes. FHOD1 and FMNL1 expression was correlated with clinical parameters, molecular features and T lymphocyte infiltration. Immunohistochemical expression of neither formin correlated with survival.

Results: Kaplan-Meier analysis associated high FHOD1 and FMNL1 mRNA expression with reduced overall survival (OS). Characterization of FHOD1 and FMNL1 in GC cells showed cytoplasmic expression along the actin filaments. Similar pattern was recapitulated in GC tissue samples. Elevated FMNL1 was associated with larger tumor size and higher disease stage. Downregulation of FHOD1 associated with TP53-mutated GC tumors. Tumor cell FHOD1 expression strongly correlated with high numbers of tumor-infiltrating CD8 + lymphocytes.

Conclusions: FHOD1 and FMNL1 proteins are expressed in the tumor cells of intestinal GC and significantly associate with clinical parameters without direct prognostic significance. FHOD1 correlates with high intratumoral CD8 + T lymphocyte infiltration in this cohort.

Keywords: FHOD1; FMNL1; Formins; Gastric cancer; T lymphocytes.

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Conflict of interest statement

The authors declare that they have no conflict of interests.

Figures

Fig. 1
Fig. 1
Prognostic significance of FHOD1 and FMNL1 mRNA expression in intestinal gastric cancer samples. a Kaplan–Meier plot (OS) of FHOD1 mRNA expression. b Kaplan–Meier plot (OS) of FMNL1 mRNA expression
Fig. 2
Fig. 2
FHOD1 and FMNL1 expression and cellular localization in gastric cancer cell lines. a, b FHOD1 and FMNL1 expression levels in AGS, MKN28, and MKN45. GAPDH was used as a control for protein loading. c, d FHOD1 and FMNL1 cellular localization and expression pattern in GC cells. Actin filaments are stained with Alexa Fluor 488-conjugated phalloidin. Scale bars: 20 µm
Fig. 3
Fig. 3
Immunohistochemical staining of FHOD1 and FMNL1 and association of high FHOD1 expression and intratumoral lymphocyte infiltration in intestinal gastric cancer. a Examples of FMNL1 and FHOD1 stainings in non-neoplastic gastric mucosa. b. Examples of FHOD1 and FMNL1 staining intensities and scoring. c, d: Analysis of correlation between FHOD1 expression and number of infiltrated lymphocytes (mean value) in central (c) and peripheral (d) tumor parts. The boxes refer to quartile distribution (25–75%) range, with the median value shown as a vertical line. Statistical significance is indicated with stars: *p < 0.05; **p < 0.01; ***p < 0.005
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