Reciprocal expression of trefoil factor‐1 and thyroid transcription factor‐1 in lung adenocarcinomas

Abstract

Molecular targeted therapies against EGFR and ALK have improved the quality of life of lung adenocarcinoma patients. However, targetable driver mutations are mainly found in thyroid transcription factor‐1 (TTF‐1)/NK2 homeobox 1 (NKX2‐1)‐positive terminal respiratory unit (TRU) types and rarely in non‐TRU types. To elucidate the molecular characteristics of the major subtypes of non‐TRU‐type adenocarcinomas, we analyzed 19 lung adenocarcinoma cell lines (11 TRU types and 8 non‐TRU types). A characteristic of non‐TRU‐type cell lines was the strong expression of TFF‐1 (trefoil factor‐1), a gastric mucosal protective factor. An immunohistochemical analysis of 238 primary lung adenocarcinomas resected at Jichi Medical University Hospital revealed that TFF‐1 was positive in 31 cases (13%). Expression of TFF‐1 was frequently detected in invasive mucinous (14/15, 93%), enteric (2/2, 100%), and colloid (1/1, 100%) adenocarcinomas, less frequent in acinar (5/24, 21%), papillary (7/120, 6%), and solid (2/43, 5%) adenocarcinomas, and negative in micropapillary (0/1, 0%), lepidic (0/23, 0%), and microinvasive adenocarcinomas or adenocarcinoma in situ (0/9, 0%). Expression of TFF‐1 correlated with the expression of HNF4‐α and MUC5AC (P < .0001, P < .0001, respectively) and inversely correlated with that of TTF‐1/NKX2‐1 (P < .0001). These results indicate that TFF‐1 is characteristically expressed in non‐TRU‐type adenocarcinomas with gastrointestinal features. The TFF‐1‐positive cases harbored KRAS mutations at a high frequency, but no EGFR or ALK mutations. Expression of TFF‐1 correlated with tumor spread through air spaces, and a poor prognosis in advanced stages. Moreover, the knockdown of TFF‐1 inhibited cell proliferation and soft‐agar colony formation and induced apoptosis in a TFF‐1‐high and KRAS‐mutated lung adenocarcinoma cell line. These results indicate that TFF‐1 is not only a biomarker, but also a potential molecular target for non‐TRU‐type lung adenocarcinomas.

Mechanisms of Dendrobium officinale polysaccharides in repairing gastric mucosal injuries based on mitogen-activated protein kinases (MAPK) signaling pathway

“…Normally, TFF1 exerts physiological functions by binding to MUC5AC mucin, its corresponding receptors, or transporters. The promotion of cell migration is an important procedure in the process of gastric mucosal repair and reconstruction [ 26 ]. TFF1 plays an important role in promoting cell migration.…”

TFF-1 Functions to Suppress Multiple Phenotypes Associated with Lung Cancer Progression

“… 42 There was also one report on lung AC that appears inconsistent with our current findings, showing that knockdown of TFF-1 inhibited cell proliferation and induced apoptosis in a TFF-1/high and KRAS- mutated lung AC cell line. 43 Again, these overall diverse effects of TFF-1 on cancer cell phenotypes may reflect a complex machinery that varies with cell type. Although discrepancies among these overall results may derived from differences in the cell lines or experimental procedures used (for example, forced expression or knockdown, constitutive or transient overexpression), the functional involvement of TFF-1 in proliferation, migration, invasion and apoptosis, seems much more dependent on upstream events.…”

<p>Prognostic Value of Gastrokine-2 (GKN2) and Its Correlation with Tumor-Infiltrating Immune Cells in Lung Cancer and Gastric Cancers</p>

“…These peptides have important functionalities, including interactions with the immune system, involvement in mucosal protection and repair, as well as in tumorigenesis. [36][37][38] Certain interactions at the structure and function levels between the GKN and TFF families were also identified. Previous reports showed that GKN2 could bind with TFF2, 39 as well as TFF1 at a protein level.…”