TSR2 overexpression inhibits proliferation and invasion of gastric cancer cells by downregulating the PI3K/AKT signaling pathway

doi:10.12122/j.issn.1673-4254.2024.05.13

Abstract

Abstract:

Objective To investigate the expression of TSR2 in gastric cancer and explore its correlation with progression of gastric cancer and the possible mechanism. Methods We retrospectively analyzed TSR2 expression in clinical specimens from 105 gastric cancer patients and the impact of TSR2 expression level on disease progression and 5-year postoperative survival of the patients. GO and KEGG enrichment analyses were used to predict the biological functions and mechanisms of TSR2. In gastric cancer MGC-803 cells with lentivirus-mediated TSR2 overexpression or knockdown, the changes in cell proliferation, invasion, and migration were assessed with CCK-8 and Transwell assays, and the expressions of p-PI3K and p-AKT were detected using Western blotting. Results TSR2 expression was significantly lower in gastric cancer tissues than in the adjacent tissues with significant correlations with CEA level, CA19-9 level, and T and N staging (P<0.05). A low TSR2 expression, CEA≥5 μg/L, CA19-9≥37 kU/L, T₃-T₄ stages, and N₂-N₃ staged were identified as independent risk factors affecting 5-year survival rate of the patients following radical surgery (P<0.05), and a high TSR2 expression was associated with a higher 5-year survival rate of the patients (P<0.001). Bioinformatics analysis suggested the functional involvement of TSR2 with the PI3K/AKT signaling pathway. MGC-803 cells overexpressing TSR2 showed significantly lowered proliferation, migration, and invasion capacities (P<0.05), while TSR2 knockdown produced the opposite effects (P<0.05). Western blotting showed that TSR2 overexpression reduced the phosphorylation of PI3K and AKT, and TSR2 knockdown caused the opposite changes in MGC-803 cells (P<0.05). Conclusion TSR2 is lowly expressed in gastric cancer tissues to adversely affect the patients' prognosis, and its overexpression inhibits gastric cancer cell proliferation, invasion, and migration possibly by downregulating the PI3K/AKT pathway.

Key words: gastric cancer, TSR2 ribosome maturation factor, PI3K/AKT, proliferation, invasion

Yongsheng XIA, Lian WANG, Xiaohua CHEN, Yulu ZHANG, Aofei SUN, Deli CHEN. TSR2 overexpression inhibits proliferation and invasion of gastric cancer cells by downregulating the PI3K/AKT signaling pathway[J]. Journal of Southern Medical University, 2024, 44(5): 913-919.

Figures/Tables 8

References 38

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Factors	n	TSR2 expression		χ ²	P
Factors	n	Low (n=53)	High (n=52)	χ ²	P
Gender				0.023	0.880
Male	74	37 (50.0%)	37 (50.0%)
Female	31	16 (51.6%)	15 (48.4%)
Age (year)				0.015	0.903
<60	41	21 (51.2%)	20 (48.8%)
≥60	64	32 (50.0%)	32 (50.0%)
CEA (μg/L)				6.940	0.008
<5	49	18 (36.7%)	31 (63.3%)
≥5	56	35 (62.5%)	21 (37.5%)
CA19-9 (kU/L)				17.720	<0.001
<37	47	13 (27.7%)	34 (72.3%)
≥37	58	40 (69.0%)	18 (31.0%)
Tumor size (cm)				2.134	0.144
<5	49	21 (42.9%)	28 (57.1%)
≥5	56	32 (57.1%)	24 (42.9%)
Histological type				1.177	0.278
Adenocarcinoma	66	36 (54.5%)	30 (45.5%)
Other	39	17 (43.6%)	22 (56.4%)
T stage				11.675	0.001
1-2	53	18 (34.0%)	35 (66.0%)
3-4	52	35 (67.3%)	17 (32.7%)
N stage				13.414	<0.001
0-1	60	21 (35.0%)	39 (65.0%)
2-3	45	32 (71.1%)	13 (28.9%)

Factors	n	TSR2 expression		χ ²	P
Factors	n	Low (n=53)	High (n=52)	χ ²	P
Gender				0.023	0.880
Male	74	37 (50.0%)	37 (50.0%)
Female	31	16 (51.6%)	15 (48.4%)
Age (year)				0.015	0.903
<60	41	21 (51.2%)	20 (48.8%)
≥60	64	32 (50.0%)	32 (50.0%)
CEA (μg/L)				6.940	0.008
<5	49	18 (36.7%)	31 (63.3%)
≥5	56	35 (62.5%)	21 (37.5%)
CA19-9 (kU/L)				17.720	<0.001
<37	47	13 (27.7%)	34 (72.3%)
≥37	58	40 (69.0%)	18 (31.0%)
Tumor size (cm)				2.134	0.144
<5	49	21 (42.9%)	28 (57.1%)
≥5	56	32 (57.1%)	24 (42.9%)
Histological type				1.177	0.278
Adenocarcinoma	66	36 (54.5%)	30 (45.5%)
Other	39	17 (43.6%)	22 (56.4%)
T stage				11.675	0.001
1-2	53	18 (34.0%)	35 (66.0%)
3-4	52	35 (67.3%)	17 (32.7%)
N stage				13.414	<0.001
0-1	60	21 (35.0%)	39 (65.0%)
2-3	45	32 (71.1%)	13 (28.9%)

Characteristic	Univariate analysis		Multivariate analysis
Characteristic	Log rank χ²	P	HR	95% CI	P
Gender (male vs female)	1.451	0.228	-	-	-
Age (≥60 years vs <60 years)	1.356	0.244	-	-	-
TSR2 expression (low vs high)	31.840	<0.001	0.418	0.201-0.871	0.020
CEA (≥5μg/L vs <5 μg/L)	18.367	<0.001	2.173	1.126-4.192	0.021
CA19-9 (≥37 kU/L vs <37 kU/L)	25.491	<0.001	3.144	1.559-6.342	0.001
Tumor size (≥5 cm vs <5 cm)	2.163	0.141	-	-	-
Histological type(adenocarcinoma vs other)	0.001	0.982	-	-	-
T stage (T₃-T₄vs T₁-T₂)	21.658	<0.001	1.991	1.034-3.832	0.039
N stage (N₂-N₃vs N₀-N₁)	26.362	<0.001	2.106	1.090-4.066	0.027

Characteristic	Univariate analysis		Multivariate analysis
Characteristic	Log rank χ²	P	HR	95% CI	P
Gender (male vs female)	1.451	0.228	-	-	-
Age (≥60 years vs <60 years)	1.356	0.244	-	-	-
TSR2 expression (low vs high)	31.840	<0.001	0.418	0.201-0.871	0.020
CEA (≥5μg/L vs <5 μg/L)	18.367	<0.001	2.173	1.126-4.192	0.021
CA19-9 (≥37 kU/L vs <37 kU/L)	25.491	<0.001	3.144	1.559-6.342	0.001
Tumor size (≥5 cm vs <5 cm)	2.163	0.141	-	-	-
Histological type(adenocarcinoma vs other)	0.001	0.982	-	-	-
T stage (T₃-T₄vs T₁-T₂)	21.658	<0.001	1.991	1.034-3.832	0.039
N stage (N₂-N₃vs N₀-N₁)	26.362	<0.001	2.106	1.090-4.066	0.027

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