Effect of the MiR-99b and MiR-135b on peritoneal carcinomatosis and liver metastasis in colorectal cancer

Aziret, Mehmet; Eskiler, Gamze Güney; Çakar, Gözde Çakırsoy; Özkan, Asuman Deveci; Ercan, Metin; Bilir, Cemil; Polat, Erdal; Koçer, Havva Belma; Yıldırım, Ebru Kayra; Duman, Mustafa

doi:10.1016/j.clinsp.2023.100271

Acessibilidade / Reportar erro

Brasil

Español English

sumário « anterior atual seguinte »

Sumário

Original articles • Clinics 78 • 2023 • https://doi.org/10.1016/j.clinsp.2023.100271 copy

Effect of the MiR-99b and MiR-135b on peritoneal carcinomatosis and liver metastasis in colorectal cancer

Authorship SCIMAGO INSTITUTIONS RANKINGS

Highlight

miRNAs are associated with colorectal cancer, peritonitis carcinomatosis, and liver metastasis.
The miR-99b, miR-135b, and Akt protein levels, which are highly expressed in peritonitis carcinomatosis and liver metastasis tissues in colorectal cancer play a fundamental role in carcinomatosis and metastasis.
While miR-99b is highest in the primary tumor, its decrease in liver metastasis suggests that miR-99b may have a protective effect against liver metastasis.
miR-135 in the highest peritonitis carcinomatosis and liver metastasis compared to the main tissue suggests that it progresses to carcinomatosis and metastasis.

Abstract

Aim

This study aimed to evaluate the expression levels of miR-99b and miR-135b in peritoneal carcinoma and liver metastases associated with Colorectal Cancer (CRC), assess their association with the intracellular signaling pathway proteins Kirsten Rat Sarcoma Virus (KRAS) and Akt, and investigate their effects on survival.

Materials and methods

Changes in the KRAS gene and Akt proteins, expression levels of miR-99b and miR-135b, and factors affecting survival were compared between colorectal cancer-associated peritoneal carcinomatosis and liver metastasis.

Results

The expression levels of miR-99b and miR-135b and the immunohistochemical grade classification score of Akt were higher in colorectal cancer, peritoneal carcinomatosis, and liver metastasis than in normal tissues (p< 0.05). MiR-99b expression was highest in CRC, whereas miR-135b expression was highest in peritoneal carcinomatosis (p< 0.05). The expression level of miR-99b decreased and that of miR-135b increased in peritoneal and liver metastases compared with that in the tumor tissue. MiR-99b, Akt, and recurrence were risk factors that affected the overall survival rate in the model of clinical predictions (p= 0.045, p= 0.006, and p= 0.012, respectively).

Conclusion

While the expression of miR-99b was highest in the primary tumor, its decrease in liver metastasis and peritoneal carcinomatosis suggests that miR-99b has a protective effect against liver metastasis and peritoneal carcinomatosis. However, the detection of miR-135b expression was highest in peritoneal carcinomatosis and liver metastasis compared with that in the colorectal cancer tissues suggesting that it facilitates peritoneal carcinomatosis and liver metastasis. Furthermore, miR-99b, KRAS mutations, and Akt are risk factors for the overall survival of colorectal cancer.

Keywords
Colorectal cancer; Liver metastasis; MiR-99b; MiR-135b; Peritonitis carcinomatosis

	Total (n= 74)	Peritoneal carcinomatosis (n= 46) (Group 1)	Liver metastasis (n= 28) (Group 2)	p-value
Age (year)	59.917 (13.500)	58.1 (12.145)	65.6 (18.610)	0.002^c c Student's t-test.
Gender, n (%)
Female	29 (39.2)	19 (25.7)	10 (13.5)	0.578^d d Continuity corrected χ2 test.
Male	45 (60.8)	27 (36.5)	18 (13.5)
ASA	3 (2.5 ‒ 3)	3 (3‒3)	3 (2‒3)	0.382^a a Mann Whitney U test.
Body Mass Index	24.3 (5.283)	22.8 (4.931)	29 (3.605)	0.06^c c Student's t-test.
Localization, n (%)				0.332^d d Continuity corrected χ2 test.
Colon	41 (55.4)	28 (37.8)	13 (17.6)
Rectum	33 (44.6)	18 (24.3)	15 (20.3)
Side, n (%)				0.595^d d Continuity corrected χ2 test.
Left	57 (77)	34 (45.9)	23 (31.1)
Right	17 (23)	12 (16.2)	5 (6.8)
KRAS status, n %)				0.968^d d Continuity corrected χ2 test.
Wild type	32 (62.7)	17 (33.3)	15 (29.4)
Mutant type	19 (37.3)	11 (21.6)	8 (15.7)
NRAS positivity	2 (2.7)	1 (2.1)	1 (3.5)	>0.999^b b Fisher's exact test.
Tumor diameter	5.2 (1.699)	5.67 (1.714)	4 (1)	0.134^c c Student's t-test.
Recurrent case, n (%)	35 (47.9)	28 (38.4)	7 (9.6)	0.004^d d Continuity corrected χ2 test.
Neoadjuvant treatment, n (%)	17 (23.6)	9 (12.5)	8 (11.1)	0.613^d d Continuity corrected χ2 test.
CEA	11.4 (5.9‒93)	12 (4‒97)	10.8 (9.65‒17.4)	0.152^a a Mann Whitney U test.
CA19-9	49.4 (7‒262)	70 (18‒256)	2 (2‒1645)	0.096^a a Mann Whitney U test.
Adjuvant treatment, n (%)	65 (94.2)	40 (58)	25 (36.2)	>0.999^b b Fisher's exact test.
Radiotherapy, n (%)	24 (35.8)	12 (17.9)	12 (17.9)	0.253^a a Mann Whitney U test.
Staging	4 (4‒4)	4 (3‒4)	4 (4‒4)	0.017^a a Mann Whitney U test.
Length of hospital	17.5 (15.5‒37.5)	18 (15‒35)	17 (16.5‒53)	0.014^a a Mann Whitney U test.
Follow-up	17.2 (13.7‒27.2)	15.6 (13.1‒20.4)	31.3 (22.9‒41.7)	<0.001^a a Mann Whitney U test.
Lymph node invasion, n (%)	51 (76.1)	34 (50.7)	17 (25.4)	0.075^d d Continuity corrected χ2 test.
Mucinous component, n (%)	25 (39.1)	22 (34.4)	3 (4.7)	0.001^d d Continuity corrected χ2 test.
Grade (median)	2 (1.5‒2)	2 (2‒2)	2 (1‒2)	0.306^a a Mann Whitney U test.
Lymphovascular invasion, n (%)	38 (70.4)	21 (38.4)	17 (31.5)	0.635^d d Continuity corrected χ2 test.
Neural invasion, n (%)	29 (67.4)	17 (39.5)	12 (27.9)	0.279^d d Continuity corrected χ2 test.

	CRC (n= 49) (%)	PC (n= 28) (%)	LVM (n= 35)^⁎⁎ ⁎⁎ Patients with Group 2 and an intensive Glisson capsule metastasis of Group 1. Definitive statistics; median (25 percentage‒75 percentage) or percentage (%). (%)	Normal Tissue (n= 25) (%)	p-value^† † Friedman test.
AKT grading					<0.001
0	1 (2)^a a CRC vs. Normal tissue Akt (p= 0.001).	1 (3.6)^b b PC vs. Normal tissue Akt (p< 0.001).	4 (11.4)^c c LVM vs. Normal tissue Akt percentage (p= 0.026).	12 (48)^a a CRC vs. Normal tissue Akt (p= 0.001). ,^b b PC vs. Normal tissue Akt (p< 0.001). ,^c c LVM vs. Normal tissue Akt percentage (p= 0.026).
1	3 (6.1)^a a CRC vs. Normal tissue Akt (p= 0.001).	1 (3.6)^b b PC vs. Normal tissue Akt (p< 0.001).	3 (8.6)^c c LVM vs. Normal tissue Akt percentage (p= 0.026).	11 (44)^a a CRC vs. Normal tissue Akt (p= 0.001). ,^b b PC vs. Normal tissue Akt (p< 0.001). ,^c c LVM vs. Normal tissue Akt percentage (p= 0.026).
2	15 (30.6)^a a CRC vs. Normal tissue Akt (p= 0.001).	4 (14.3)^b b PC vs. Normal tissue Akt (p< 0.001).	13 (20)^c c LVM vs. Normal tissue Akt percentage (p= 0.026).	2 (8)^a a CRC vs. Normal tissue Akt (p= 0.001). ,^b b PC vs. Normal tissue Akt (p< 0.001). ,^c c LVM vs. Normal tissue Akt percentage (p= 0.026).
3	18 (36.7)^a a CRC vs. Normal tissue Akt (p= 0.001).	7 (25)^b b PC vs. Normal tissue Akt (p< 0.001).	7 (22.9)^c c LVM vs. Normal tissue Akt percentage (p= 0.026).
4	12 (24.5)^a a CRC vs. Normal tissue Akt (p= 0.001).	15 (53.6)^b b PC vs. Normal tissue Akt (p< 0.001).	8 (22.9)^c c LVM vs. Normal tissue Akt percentage (p= 0.026).
Akt^* ⁎ Akt severity percentage (%). (%)	70.0 (42.5‒80.0)^d d CRC vs. Normal tissue Akt (%) (p< 0.01).	80.0 (62.5‒80.0)^e e PC vs. Normal tissue Akt percentage (p< 0.01).	40.0 (30.0‒77.5)^f f LVM vs. Normal tissue Akt) (p< 0.01).	5.0 (5.0‒15.0)^d d CRC vs. Normal tissue Akt (%) (p< 0.01). ,^e e PC vs. Normal tissue Akt percentage (p< 0.01). ,^f f LVM vs. Normal tissue Akt) (p< 0.01).	<0.001

A	Tumor		Peritoneal carcinomatosis		Liver metastasis
	Fold-change	p	Fold-change	p	Fold-change	p
Hsa-miR-99b	19.7	0.001	12.55	0.001	3.97	0.038
Hsa-miR-135b	3.53	0.027	9.68	0.001	5.23	0.002
			Peritoneal carcinomatosis		Liver metastasis
B			Fold-change	p	Fold-change	p
Hsa-miR-99			0.64	0.145	0.2	0.001
Hsa-miR-135b			2.74	0.001	1.48	0.116

	Hazard ratio	95% Confidential Interval		Wald	p-value
	Hazard ratio	Lower bound	Upper bound	Wald	p-value
Model 1
Localization (Rectum)	1.068	0.384	2.970	0.016	0.899
T-staging	2.491	0.828	7.489	2.639	0.104
Lympho-vascular invasion	1.951	0.692	5.505	1.597	0.206
Neural invasion	6.264	1.482	26.470	6.227	0.013
CRC Akt (%) (> 57.5)	4.591	1.527	13.801	7.367	0.007
KRAS mutation	2.757	1.039	7.314	4.148	0.042
Model 2
Age	1.008	0.861	1.179	0.009	0.925
Staging	0.070	0.004	1.298	3.188	0.074
Recurrent case	147.100	2.951	7332.552	6.263	0.012
Lymph node positivity	9.552	0.616	148.239	2.602	0.107
Neural invasion	92.033	0.537	15762.401	2.970	0.085
CRC Akt (%) (> 57.5)	1.096	1.026	1.170	7.492	0.006
miR-99b-CRC	1.188	1.004	1.406	4.008	0.045
KRAS mutation	12.734	0.361	449.481	1.958	0.162

Faculdade de Medicina / USP Rua Dr Ovídio Pires de Campos, 225 - 6 and., 05403-010 São Paulo SP - Brazil, Tel.: (55 11) 2661-6235 - São Paulo - SP - Brazil
E-mail: clinics@hc.fm.usp.br

Acompanhe os números deste periódico no seu leitor de RSS

[1] * Corresponding author. E-mail address:mhmtaziret@gmail.com (M. Aziret).