KCNK9 mediates the inhibitory effects of genistein on hepatic metastasis from colon cancer

Cheng, Yuan; Tang, Yi; Tan, Yiming; Li, Juan; Zhang, Xuping

doi:10.1016/j.clinsp.2022.100141

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Sumário

Original articles • Clinics 78 • 2023 • https://doi.org/10.1016/j.clinsp.2022.100141 copy

KCNK9 mediates the inhibitory effects of genistein on hepatic metastasis from colon cancer

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Objective:

The tyrosine-protein kinase inhibitor, genistein, can inhibit cell malignant transformation and has an antitumor effect on various types of cancer. It has been shown that both genistein and KNCK9 can inhibit colon cancer. This research aimed to investigate the suppressive effects of genistein on colon cancer cells and the association between the application of genistein and KCNK9 expression level.

Methods:

The Cancer Genome Atlas (TCGA) database was used to study the correlation between the KCNK9 expression level and the prognosis of colon cancer patients. HT29 and SW480 colon cancer cell lines were cultured to examine the inhibitory effects of KCNK9 and genistein on colon cancer in vitro, and a mouse model of colon cancer with liver metastasis was established to verify the inhibitory effect of genistein in vivo.

Results:

KCNK9 was overexpressed in colon cancer cells and was associated with a shorter Overall Survival (OS), a shorter Disease-Specific Survival (DFS), and a shorter Progression-Free Interval (PFI) of colon cancer patients. In vitro experiments showed that downregulation of KCNK9 or genistein application could suppress cell proliferation, migration, and invasion abilities, induce cell cycle quiescence, promote cell apoptosis, and reduce epithelialmesenchymal transition of the colon cancer cell line. In vivo experiments revealed that silencing of KCNK9 or application of genistein could inhibit hepatic metastasis from colon cancer. Additionally, genistein could inhibit KCNK9 expression, thereby attenuating Wnt/β-catenin signaling pathway.

Conclusion:

Genistein inhibited the occurrence and progression of colon cancer through Wnt/β-catenin signaling pathway that could be mediated by KCNK9.

Keywords:
KCNK9; Genistein; Colon cancer; Metastasis

HIGHLIGHTS

High KCNK9 expression level is correlated with colon cancer patients’ poor survival.

KCNK9 promotes proliferation, migration, invasion, EMT, and Wnt signaling pathway.

KCNK9 mediates the inhibitory effects of genistein on colon cancer liver metastasis.

Characteristics	Low KCNK9 expression	High KCNK9 expression	p
N	239	239
T stage, n (%)			0.533
T1	7 (1.5%)	4 (0.8%)
T2	45 (9.4%)	38 (8%)
T3	155 (32.5%)	168 (35.2%)
T4	32 (6.7%)	28 (5.9%)
N stage, n (%)			0.013
N0	157 (32.8%)	127 (26.6%)
N1	49 (10.3%)	59 (12.3%)
N2	33 (6.9%)	53 (11.1%)
M stage, n (%)			0.004
M0	182 (43.9%)	167 (40.2%)
M1	21 (5.1%)	45 (10.8%)
Pathological stage, n (%)			0.004
Stage I	45 (9.6%)	36 (7.7%)
Stage II	106 (22.7%)	81 (17.3%)
Stage III	64 (13.7%)	69 (14.8%)
Stage IV	21 (4.5%)	45 (9.6%)
Primary therapeutic outcomes, n (%)			0.213
PD	9 (3.6%)	16 (6.4%)
SD	1 (0.4%)	3 (1.2%)
PR	9 (3.6%)	4 (1.6%)
CR	102 (40.8%)	106 (42.4%)
Gender, n (%)			1.000
Female	113 (23.6%)	113 (23.6%)
Male	126 (26.4%)	126 (26.4%)
Race, n (%)			0.487
Asian	4 (1.3%)	7 (2.3%)
Black or African American	34 (11.1%)	29 (9.5%)
White	111 (36.3%)	121 (39.5%)
Residual tumor, n (%)			0.042
R0	179 (47.9%)	167 (44.7%)
R1	1 (0.3%)	3 (0.8%)
R2	7 (1.9%)	17 (4.5%)
CEA level, n (%)			0.092
≤ 5	100 (33%)	96 (31.7%)
> 5	43 (14.2%)	64 (21.1%)
Perineural invasion, n (%)			0.899
No	68 (37.6%)	67 (37%)
Yes	22 (12.2%)	24 (13.3%)
Lymphatic invasion, n (%)			0.050
No	141 (32.5%)	125 (28.8%)
Yes	72 (16.6%)	96 (22.1%)
History of colon polyps, n (%)			0.026
No	121 (29.7%)	141 (34.6%)
Yes	85 (20.8%)	61 (15%)
Colon polyps present, n (%)			0.704
No	80 (32.1%)	82 (32.9%)
Yes	40 (16.1%)	47 (18.9%)
Neoplasm type, n (%)			1.000
Colon adenocarcinoma	239 (50%)	239 (50%)
Rectum adenocarcinoma	0 (0%)	0 (0%)
Age, median (IQR)	69 (60, 79)	69 (58, 76.5)	0.345
Height, median (IQR)	167.8 (160, 175)	170.05 (163, 176)	0.065
Weight, median (IQR)	80.2 (64.1, 97.5)	81 (67.08, 91.03)	0.623
BMI, median (IQR)	27.22 (23.81, 34.94)	27.1 (24.03, 31.71)	0.642

Characteristics	Total (N)	Hazard ratio (95% CI)	p
T stage	476
T1 & T2	94	Reference
T3 & T4	382	3.072 (1.423‒6.631)	0.004
N stage	477
N0	283	Reference
N1	108	1.681 (1.019‒2.771)	0.042
N2	86	4.051 (2.593‒6.329)	< 0.001
M stage	414
M0	348	Reference
M1	66	4.193 (2.683‒6.554)	< 0.001
Pathological stage	466
I & II stage	267	Reference
III & IV stage	199	2.947 (1.942‒4.471)	< 0.001
Lymphatic invasion	433
No	265	Reference
Yes	168	2.450 (1.614‒3.720)	< 0.001
Perineural invasion	181
No	135	Reference
Yes	46	1.940 (0.982‒3.832)	0.056
Primary therapeutic outcomes	250
PD	25	Reference
SD	4	0.930 (0.120‒7.183)	0.944
PR	13	0.271 (0.062‒1.191)	0.084
CR	208	0.087 (0.044‒0.173)	< 0.001
Gender	477
Female	226	Reference
Male	251	1.101 (0.746‒1.625)	0.627
Race	306
Asian	11	Reference
Black or African American	63	0.927 (0.208‒4.133)	0.921
White	232	0.810 (0.196‒3.346)	0.771
Age (years old)	477
≤ 65	194	Reference
> 65	283	1.610 (1.052‒2.463)	0.028
Weight (kg)	273
≤ 90	189	Reference
> 90	84	0.601 (0.292‒1.238)	0.167
Height (cm)	256
< 170	127	Reference
≥ 170	129	0.786 (0.445‒1.389)	0.407
BMI (kg/m²2 Bray F, Ferlay J, Soerjomataram I, Siegel R, Torre L, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68(6):394–424.)	256
< 25	87	Reference
≥ 25	169	0.549 (0.311‒0.969)	0.038
Residual tumor	373
R0	345	Reference
R1 & R2	28	4.364 (2.401‒7.930)	< 0.001
CEA level	302
≤ 5	195	Reference
> 5	107	3.128 (1.788‒5.471)	< 0.001
History of colon polyps	407
No	262	Reference
Yes	145	0.741 (0.442‒1.242)	0.255
Existence of colon polyps	249
No	162	Reference
Yes	87	1.324 (0.738‒2.373)	0.346
KCNK9	477	1.375 (1.052‒1.797)	0.020

Characteristics	Total (N)	Hazard ratio (95% CI)	p
T stage	460
T1 & T2	93	Reference
T3 & T4	367	7.758 (1.896‒31.745)	0.004
N stage	461
N0	275	Reference
N1	105	2.601 (1.353‒5.000)	0.004
N2	81	6.357 (3.512‒11.504)	< 0.001
M stage	399
M0	334	Reference
M1	65	7.833 (4.597‒13.346)	< 0.001
Pathological stage	451
I & II stage	259	Reference
III & IV stage	192	6.085 (3.235‒11.447)	< 0.001
Lymphatic invasion	422
No	255	Reference
Yes	167	4.133 (2.361‒7.235)	< 0.001
Perineural invasion	180
No	134	Reference
Yes	46	2.977 (1.325‒6.686)	0.008
Primary therapeutic outcomes	249
PD	24	Reference
SD	4	0.000 (0.000‒Inf)	0.998
PR	13	0.241 (0.055‒1.060)	0.060
CR	208	0.032 (0.012‒0.082)	< 0.001
Gender	461
Female	220	Reference
Male	241	1.142 (0.697‒1.871)	0.599
Race	290
Asian	11	Reference
Black or African American	63	1.439 (0.184‒11.255)	0.729
White	216	0.702 (0.094‒5.263)	0.731
Age (years old)	461
≤ 65	191	Reference
> 65	270	1.165 (0.702‒1.933)	0.555
Weight (kg)	258
≤ 90	174	Reference
> 90	84	0.907 (0.380‒2.162)	0.825
Height (cm)	241
< 170	122	Reference
≥ 170	119	0.658 (0.284‒1.525)	0.329
BMI (kg/m²2 Bray F, Ferlay J, Soerjomataram I, Siegel R, Torre L, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68(6):394–424.)	241
< 25	79	Reference
≥ 25	162	0.979 (0.415‒2.310)	0.961
Residual tumor	373
R0	345	Reference
R1 & R2	28	6.107 (3.225‒11.563)	< 0.001
CEA level	301
≤ 5	194	Reference
> 5	107	3.018 (1.543‒5.901)	0.001
History of colon polyps	396
No	253	Reference
Yes	143	0.907 (0.497‒1.657)	0.752
Existence of colon polyps	243
No	161	Reference
Yes	82	1.397 (0.648‒3.011)	0.393
KCNK9	461	1.518 (1.105‒2.086)	0.010

Characteristics	Total (N)	Hazard ratio (95% CI)	p
T stage	476
T1 & T2	94	Reference
T3 & T4	382	3.111 (1.631‒5.936)	< 0.001
N stage	477
N0	283	Reference
N1	108	1.564 (0.993‒2.465)	0.054
N2	86	4.761 (3.188‒7.111)	< 0.001
M stage	414
M0	348	Reference
M1	66	5.811 (3.921‒8.611)	< 0.001
Pathological stage	466
I & II stage	267	Reference
III & IV stage	199	3.061 (2.120‒4.419)	< 0.001
Lymphatic invasion	433
No	265	Reference
Yes	168	2.433 (1.679‒3.525)	< 0.001
Perineural invasion	181
No	135	Reference
Yes	46	2.362 (1.279‒4.363)	0.006
Primary therapeutic outcomes	250
PD	25	Reference
SD	4	0.815 (0.108‒6.163)	0.843
PR	13	0.321 (0.110‒0.941)	0.038
CR	208	0.085 (0.048‒0.152)	< 0.001
Gender	477
Female	226	Reference
Male	251	1.166 (0.822‒1.656)	0.389
Race	306
Asian	11	Reference
Black or African American	63	0.835 (0.247‒2.824)	0.772
White	232	0.530 (0.164‒1.711)	0.289
Age (years old)	477
≤ 65	194	Reference
> 65	283	0.975 (0.683‒1.391)	0.888
Weight (kg)	273
≤ 90	189	Reference
> 90	84	0.950 (0.568‒1.589)	0.845
Height (cm)	256
< 170	127	Reference
≥ 170	129	1.198 (0.741‒1.939)	0.461
BMI (kg/m²2 Bray F, Ferlay J, Soerjomataram I, Siegel R, Torre L, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68(6):394–424.)	256
< 25	87	Reference
≥ 25	169	1.186 (0.709‒1.986)	0.515
Residual tumor	373
R0	345	Reference
R1 & R2	28	4.343 (2.554‒7.385)	< 0.001
CEA level	302
≤ 5	195	Reference
> 5	107	2.900 (1.844‒4.561)	< 0.001
History of colon polyps	407
No	262	Reference
Yes	145	0.744 (0.482‒1.150)	0.183
Existence of colon polyps	249
No	162	Reference
Yes	87	0.996 (0.607‒1.634)	0.987
KCNK9	477	1.296 (1.017‒1.650)	0.036

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[1] *Corresponding author. E-mail address:Xuping_Zhang@163.com (X. Zhang).