TIMP1 promotes cell proliferation and invasion capability of right-sided colon cancers via the FAK/Akt signaling pathway

被引：27

作者：

Ma, Beibei ^{[1
]}

Ueda, Hiroyuki ^{[1
]}

Okamoto, Koichi ^{[1
]}

Bando, Masahiro ^{[1
]}

Fujimoto, Shota ^{[1
]}

Okada, Yasuyuki ^{[1
]}

Kawaguchi, Tomoyuki ^{[1
]}

Wada, Hironori ^{[1
]}

Miyamoto, Hiroshi ^{[1
]}

Shimada, Mitsuo ^{[2
]}

Sato, Yasushi ^{[3
]}

Takayama, Tetsuji ^{[1
]}

机构：

[1] Tokushima Univ, Inst Biomed Sci, Dept Gastroenterol & Oncol, Grad Sch, Tokushima 7708503, Japan

[2] Tokushima Univ, Inst Biomed Sci, Dept Surg, Grad Sch, Tokushima, Japan

[3] Tokushima Univ, Inst Biomed Sci, Dept Community Med Gastroenterol & Oncol, Grad Sch, Tokushima, Japan

来源：

CANCER SCIENCE | 2022年 / 113卷 / 12期

关键词：

colorectal cancer; organoids; prognosis; TIMP1; tumor location; METASTATIC COLORECTAL-CANCER; TISSUE INHIBITORS; TUMOR SIDE; PROGNOSIS; ORGANOIDS; CYTOKINE; ADENOMA; DISTAL;

D O I：

10.1111/cas.15567

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Although right-sided colorectal cancer (CRC) shows a worse prognosis than left-sided CRC, the underlying mechanism remains unclear. We established patient-derived organoids (PDOs) from left- and right-sided CRCs and directly compared cell proliferation and invasion capability between them. We then analyzed the expression of numerous genes in signal transduction pathways to clarify the mechanism of the differential prognosis. Cell proliferation activity and invasion capability in right-sided cancer PDOs were significantly higher than in left-sided cancer PDOs and normal PDOs, as revealed by Cell Titer Glo and transwell assays, respectively. We then used quantitative RT-PCR to compare 184 genes in 30 pathways among right-sided and left-sided cancer and normal PDOs and found that the TIMP1 mRNA level was highest in right-sided PDOs. TIMP1 protein levels were upregulated in right-sided PDOs compared with normal PDOs but was downregulated in left-sided PDOs. TIMP1 knockdown with shRNA significantly decreased cell proliferation activity and invasion capability in right-sided PDOs but not in left-sided PDOs. Moreover, TIMP1 knockdown significantly decreased pFAK and pAkt expression levels in right-sided PDOs but not in left-sided PDOs. A database analysis of The Cancer Genome Atlas revealed that TIMP1 expression in right-sided CRCs was significantly higher than in left-sided CRCs. Kaplan-Meier survival analysis showed significantly shorter overall survival in high-TIMP1 patients versus low-TIMP1 patients with right-sided CRCs but not left-sided CRCs. Our data suggest that TIMP1 is overexpressed in right-sided CRCs and promotes cell proliferation and invasion capability through the TIMP1/FAK/Akt pathway, leading to a poor prognosis. The TIMP1/FAK/Akt pathway can be a target for therapeutic agents in right-sided CRCs.

引用

页码：4244 / 4257

页数：14

共 41 条

[1]

[Anonymous], 2023, CA Cancer J Clin, DOI DOI 10.3322/caac.21772

[2] Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials [J].

Arnold, D. ;

Lueza, B. ;

Douillard, J. -Y. ;

Peeters, M. ;

Lenz, H. -J. ;

Venook, A. ;

Heinemann, V. ;

Van Cutsem, E. ;

Pignon, J. -P. ;

Tabernero, J. ;

Cervantes, A. ;

Ciardiello, F. .

ANNALS OF ONCOLOGY, 2017, 28 (08) :1713-1729

[3] Influence of anatomical subsite on the incidence of microsatellite instability, and KRAS and BRAF mutation rates in patients with colon carcinoma [J].

Benedix, Frank ;

Meyer, Frank ;

Kube, Rainer ;

Kropf, Siegfried ;

Kuester, Doerthe ;

Lippert, Hans ;

Roessner, Albert ;

Krueger, Sabine .

PATHOLOGY RESEARCH AND PRACTICE, 2012, 208 (10) :592-597

[4] Preoperative plasma TIMP-1 is an independent prognostic indicator in patients with primary colorectal cancer: A prospective validation study [J].

Birgisson, Helgi ;

Nielsen, Hans J. ;

Christensen, Ib Jarle ;

Glimelius, Bengt ;

Brunner, Nils .

EUROPEAN JOURNAL OF CANCER, 2010, 46 (18) :3323-3331

[5] Serum MMP-8 and TIMP-1 predict prognosis in colorectal cancer [J].

Bockelman, Camilla ;

Beilmann-Lehtonen, Ines ;

Kaprio, Tuomas ;

Koskensalo, Selja ;

Tervahartiala, Taina ;

Mustonen, Harri ;

Stenman, Ulf-Hakan ;

Sorsa, Timo ;

Haglund, Caj .

BMC CANCER, 2018, 18

[6] Primary tumor sidedness has an impact on prognosis and treatment outcome in metastatic colorectal cancer: results from two randomized first-line panitumumab studies [J].

Boeckx, N. ;

Koukakis, R. ;

de Beeck, K. Op ;

Rolfo, C. ;

Van Camp, G. ;

Siena, S. ;

Tabernero, J. ;

Douillard, J. -Y. ;

Andre, T. ;

Peeters, M. .

ANNALS OF ONCOLOGY, 2017, 28 (08) :1862-1868

[7] COLORECTAL-CANCER - EVIDENCE FOR DISTINCT GENETIC CATEGORIES BASED ON PROXIMAL OR DISTAL TUMOR LOCATION [J].

BUFILL, JA .

ANNALS OF INTERNAL MEDICINE, 1990, 113 (10) :779-788

[8] Higher levels of TIMP-1 expression are associated with a poor prognosis in triple-negative breast cancer [J].

Cheng, Guangcun ;

Fan, Xuemei ;

Hao, Mingang ;

Wang, Jinglong ;

Zhou, Xiaoming ;

Sun, Xueqing .

MOLECULAR CANCER, 2016, 15

[9] Rho-associated kinase signalling and the cancer microenvironment: novel biological implications and therapeutic opportunities [J].

Chin, Venessa T. ;

Nagrial, Adnan M. ;

Chou, Angela ;

Biankin, Andrew V. ;

Gill, Anthony J. ;

Timpson, Paul ;

Pajic, Marina .

EXPERT REVIEWS IN MOLECULAR MEDICINE, 2015, 17

[10] Tumor Side as Model of Integrative Molecular Classification of Colorectal Cancer [J].

Dienstmann, Rodrigo .

CLINICAL CANCER RESEARCH, 2018, 24 (05) :989-990

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