FERM domain-containing protein FRMD6 activates the mTOR signaling pathway and promotes lung cancer progression

doi:10.1007/s11684-022-0959-5

Front. Med.

2023, Vol. 17

Issue (4) : 714-728 https://doi.org/10.1007/s11684-022-0959-5

RESEARCH ARTICLE

FERM domain-containing protein FRMD6 activates the mTOR signaling pathway and promotes lung cancer progression

Tianzhuo Wang, Huiying Guo, Lei Zhang, Miao Yu, Qianchen Li, Jing Zhang, Yan Tang, Hongquan Zhang, Jun Zhan(

)

Program for Cancer and Cell Biology, Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences; Peking University International Cancer Institute; MOE Key Laboratory of Carcinogenesis and Translational Research and State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China

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Abstract

FRMD6, a member of the 4.1 ezrin–radixin–moesin domain-containing protein family, has been reported to inhibit tumor progression in multiple cancers. Here, we demonstrate the involvement of FRMD6 in lung cancer progression. We find that FRMD6 is overexpressed in lung cancer tissues relative to in normal lung tissues. In addition, the enhanced expression of FRMD6 is associated with poor outcomes in patients with lung squamous cell carcinoma (n = 75, P = 0.0054) and lung adenocarcinoma (n = 94, P = 0.0330). Cell migration and proliferation in vitro and tumor formation in vivo are promoted by FRMD6 but are suppressed by the depletion of FRMD6. Mechanistically, FRMD6 interacts and colocalizes with mTOR and S6K, which are the key molecules of the mTOR signaling pathway. FRMD6 markedly enhances the interaction between mTOR and S6K, subsequently increasing the levels of endogenous pS6K and downstream pS6 in lung cancer cells. Furthermore, knocking out FRMD6 inhibits the activation of the mTOR signaling pathway in Frmd6^−/− gene KO MEFs and mice. Altogether, our results show that FRMD6 contributes to lung cancer progression by activating the mTOR signaling pathway.

Keywords FRMD6 lung cancer mTOR pathway

Corresponding Author(s): Jun Zhan

Just Accepted Date: 10 February 2023 Online First Date: 17 April 2023 Issue Date: 12 October 2023

Cite this article:

Tianzhuo Wang,Huiying Guo,Lei Zhang, et al. FERM domain-containing protein FRMD6 activates the mTOR signaling pathway and promotes lung cancer progression[J]. Front. Med., 2023, 17(4): 714-728.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-022-0959-5
https://academic.hep.com.cn/fmd/EN/Y2023/V17/I4/714

Reagent or resource	Source	Identifier
Antibodies
Rabbit monoclonal antibody anti-FRMD6 (D8X3R)	Cell Signaling Technology	Cat#14688; RRID:AB_2722638
Rabbit monoclonal antibody anti-mTOR (7C10)	Cell Signaling Technology	Cat#2983: RRID:AB_2105622
Rabbit polyclonal antibody anti-Phospho-mTOR (Ser2481)	Cell Signaling Technology	Cat#2974; RRID:AB_2262884
Rabbit monoclonal antibody anti-S6K (49D7)	Cell Signaling Technology	Cat#2708; RRID:AB_390722
Rabbit polyclonal antibody anti-Phospho-S6K (Thr389)	Cell Signaling Technology	Cat#9205; RRID:AB_330944
Rabbit monoclonal antibody anti-S6 (5G10)	Cell Signaling Technology	Cat#2217; RRID:AB_2262884
Rabbit monoclonal antibody anti-Phospho-S6 (Ser235/236)	Cell Signaling Technology	Cat#4858; RRID:AB_916156
Rabbit polyclonal antibody anti- FRMD6/Willin	Abcam	Cat#ab218209; RRID:AB_2877174
Rabbit polyclonal antibody anti-HA	Abcam	Cat#ab9110; RRID:AB_307019
Mouse monoclonal anti-Flag	Sigma-Aldrich	Cat#F1804; RRID:AB_262044
Mouse monoclonal anti-actin	ZSGB-Bio	Cat#TA-09; RRID:AB_2636897
Mouse monoclonal anti-actin (2Q1055)	Santa Cruz Biotechnology	Cat#sc-58673; RRID:AB_2223345
Anti-Rabbit IgG HP-linked	Sangon Biotech	Cat#D110058
Bacterial and virus strains
DH5α	TIANGEN	Cat#CB101-03
Chemicals, peptides, and recombinant proteins
Anti-Flag^® M2 Beads	Sigma-Aldrich	Cat#M8823
Protein A-Agarose	Santa Cruz Biotechnology	Cat#sc-2001
Protein G-Agarose	Santa Cruz Biotechnology	Cat#sc-2003
Protease inhibitor cocktail	Roche	Cat#11836170001
PhosSTOP	Roche	Cat#4906845001
Puromycin	Yeasen	Cat#60210ES25; Cas 58-58-2
G418	Life	Cat#10131027
Critical commercial assays
Lipofectamine 2000	Invitrogen	Cat#11668030
RNAi MAX	Invitrogen	Cat#13778100
Experimental models: cell lines
Human: HEK-293T	ATCC	N/A
Human: NCI-H1299	ATCC	N/A
Human: A549	ATCC	N/A
Human: HeLa	ATCC	N/A
Oligonucleotides
FRMD6 siRNA-1	CAUCCAAGAUGCUUUUCCATT	N/A
FRMD6 siRNA-2	GCAGCUCAAUGACCAGUCATT	N/A
Recombinant DNA
CMV-3 × Flag-FRMD6	This manuscript	N/A
CMV6-AC-3HA-S6K	This manuscript	N/A
pLVX-Flag-FRMD6	This manuscript	N/A
CRISPR/Cas9-FRMD6	This manuscript	N/A
Software and algorithms
GraphPad Prism 8.0	GraphPad software
Image J	NIH
TCGA	PanCancer Atlas

Tab.1 Key resources

Fig.1 Elevated FRMD6 predicts poor outcomes in lung cancer. (A, B) FRMD6 mRNA levels in LUSC and LUAD were evaluated by analyzing the TCGA RNA sequence data set (TCGA, PanCancer Atlas). FRMD6 mRNA was significantly higher in LUSC (n = 49, P = 9e−13) and LUAD (n = 57, P = 9.1e−7) than in adjacent tissues. (C) FRMD6 levels were detected by IHC in human normal lung and lung cancer tissues with the anti-FRMD6 antibody. Representative images of 1+ (low expression) and 2+ and 3+ (strong expression) of FRMD6 are shown. Scale bars: 50 μm. (D) Semiquantitative analyses were performed to evaluate the FRMD6 levels in LUSC and LUAD samples relative to those in normal lung tissues. **** P < 0.0001, Student’s t-test. (E) Kaplan–Meier analyses were performed on patients with LUSC and LUAD with the high expression (≥2+ ) and low expression ( < 2+ ) of FRMD6. FRMD6 was found to predict the poor outcome of lung cancer in LUSC through the logrank test at P = 0.0054 and in LUAD through the logrank test at P = 0.0330.

Tab.2 FRMD6 expression and clinicopathological information of patients with LUAD (n = 94)

Fig.2 FRMD6 promotes the proliferation and migration of lung cancer cells. (A) Flag-FRMD6 was transiently transfected into H1299 cells controlled with Flag transfection, and transfection efficiency was detected through WB analysis with the indicated antibodies. (B) Then, Transwell assay was performed to detect the migration ability of Flag-FRMD6-transfected H1299 cells controlled with Flag-transfected H1299 cells. Data are presented as mean ± SEM from three independent experiments. *** P < 0.001, Student’s t-test. Representative images are shown in the bottom panel. (C) pLVX-Flag-Vector and pLVX-Flag-FRMD6 were stably transfected into H1299 cells, and transfection efficiency was detected through WB analysis with the indicated antibodies. (D) Subsequently, the CCK-8 assay was performed to detect the proliferation ability of H1299 cells stably transfected with pLVX-Flag-FRMD6 controlled with H1299 cells stably transfected with Flag. Data are presented as mean ± SEM from three independent experiments. * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001, Sidak’s multiple comparisons test. (E) H1299 cells were transfected with control siRNA or FRMD6 siRNA, and knockdown efficiency was detected through WB analysis with the FRMD6 antibody. (F) CCK-8 assays were performed to detect the proliferation ability of FRMD6 knockdown cells controlled with con siRNA transfection. Data are presented as mean ± SEM from three independent experiments. ** P < 0.01, *** P < 0.001, **** P < 0.0001, Sidak’s multiple comparisons test. (G) Colony formation assays were performed to detect the proliferation ability of cells. Data are presented as mean ± SEM from three independent experiments. *** P < 0.001, Student’s t-test. Representative colony images are shown in the bottom panel. (H) Transwell assay was performed to detect the migration ability of cells. Data are presented as mean ± SEM from three independent experiments. *** P < 0.001, Student’s t-test. Representative images are shown in the bottom panel. (I) Xenograft experiment was performed on BALB/c nude mice (n = 4) injected with untreated H1299 cells and H1299 cells transfected with FRMD6 siRNA (4 × 10⁶ cells per mouse). Tumor diameter was measured every 3 days for 26 days, and tumor volumes were calculated as V = ab²/2. Data are presented as mean ± SEM. * P < 0.05, Student’s t-test. (J) Mice were sacrificed, and tumors were dissected and photographed on the 26th day after cell injection. (K) Measurement of the weight of tumors at day 26. Data are presented as mean ± SEM. * P < 0.05, Student’s t-test.

Fig.3 FRMD6 interacts with mTOR signaling pathway proteins. (A) HEK-293T cells expressing Flag-FRMD6 were lysed and used for immunoprecipitation then subjected to Coomassie brilliant blue staining. The results indicated that FRMD6 interacts with mTOR. (B) Mass spectrometry molecules with abundance ratios (Flag-FRMD6/Flag) greater than 4 were screened for KEGG pathway enrichment analysis. The top 10 pathways indicated that FRMD6 significantly regulates the mTOR signaling pathway. (C) HEK-293T (left) and H1299 cells (right) were transfected with Flag or Flag-FRMD6, subjected to Co-IP with the Flag-antibody, then subjected to WB with the indicated antibodies. The mTOR signaling pathway members mTOR, S6K, and S6 were all proven to interact with FRMD6. (D) Co-IP assays were performed by using lysates from HEK-293T cells with control IgG or anti-FRMD6 antibody. Then, WB was performed with anti-mTOR, anti-S6K, and anti-S6 antibodies. (E) H1299 cells were transfected with Flag-FRMD6 and subjected to double immunostaining with anti-Flag mouse (green) and anti-mTOR rabbit (red). (F) HeLa cells were subjected to double immunostaining with anti-Flag mouse (green) and anti-S6K rabbit (red), then visualized with confocal microscopy (Zeiss LSM 780 with Airyscan). The magnification of selected areas is shown (enlarged). White arrows show yellow points indicating colocalization. Scale bars: 5 μm.

Fig.4 FRMD6 contributes to the activation of the mTOR signaling pathway. (A) H1299 cells transfected with Flag or Flag-FRMD6 and the activation of the mTOR signaling pathway proteins mTOR, pmTOR, S6K, pS6K, S6, and pS6 were detected with specific antibodies. FRMD6 was found to promote the activation of the mTOR signaling pathway. (B, C) FRMD6 was knocked down by transfecting specific siRNAs into H1299, A549, SW480, and PANC1 cells. The activation of mTOR signaling pathway proteins was detected with the indicated antibodies. (D) Vector- or CRISPR/Cas9-mediated FRMD6 KO in H1299 cells followed by WB with the indicated antibodies. The loss of FRMD6 was found to inactivate the mTOR signaling pathway. (E) HEK-293T and H1299 cells were co-transfected with Flag or Flag-FRMD6 and HA-S6K; subjected to Co-IP with the HA antibody; then used for WB with the indicated mTOR, S6, Flag, and HA antibodies. FRMD6 was found to promote the combination between mTOR and S6K. (F) Top: FRMD6 and mTOR signaling pathway protein levels were examined in the indicated lung cancer cell lines by WB. Bottom: qualification for (F). Data are presented as mean ± SEM. *P < 0.05 by Student’s t-test. FRMD6 high: H23, H1299. FRMD6 low: A549, H157, Calu-3.

Fig.5 FRMD6 deficiency inhibits mTOR signaling pathway in vivo. (A) Schematic of Frmd6 KO mouse generation by using CRISPR/Cas9 technology. (B) Genotype identification of Frmd6 KO mice by PCR. (C) Genotype ratios of born mice (n = 604) after mating FRMD6 heterozygote mice. P < 0.0001, chi-square test. (D) Gross morphology of WT and Frmd6 KO mice at day 12. Compared with WT mice, KO mice were dramatically underdeveloped, thin, and small. (E) Representative WB analysis of mTOR signaling pathway protein levels in WT and Frmd6 KO MEFs (E13.5) with the indicated antibodies. (F) Representative WB analysis of mTOR signaling pathway protein levels in the heart, spleen, and ovarian tissues of WT and KO mice with the indicated antibodies. FRMD6 KO was found to inhibit the mTOR signaling pathway in vivo.

Fig.6 FRMD6 is positively correlated with mTOR signaling activation in lung cancer. (A) Expression of FRMD6 and p-S6 in LUAD and human normal lung tissues detected via IHC analysis. Representative images of 3+ (strong expression), 2+ (moderate expression), 1+ (low expression), and 0 (negative) are shown. Scale bars: 50 μm. (B) Working model: FRMD6, as a scaffold protein, promotes the combination of mTOR with S6K to stimulate the phosphorylation of S6K, then promotes cell proliferation and lung cancer progression. By contrast, the low expression of FRMD6 inhibits the phosphorylation of the mTOR cascade, as well as cell proliferation and migration and lung cancer progression.

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