Characterization of the expression of LAT1 as a prognostic indicator and a therapeutic target in renal cell carcinoma

被引：41

作者：

Higuchi, Kosuke ^{[1
,2
]}

Sakamoto, Shinichi ^{[2
]}

Ando, Keisuke ^{[1
,2
]}

Maimaiti, Maihulan ^{[2
]}

Takeshita, Nobushige ^{[1
,2
]}

Okunushi, Kentaro ^{[1
]}

Reien, Yoshie ^{[1
]}

Imamura, Yusuke ^{[2
]}

Sazuka, Tomokazu ^{[2
]}

Nakamura, Kazuyoshi ^{[2
]}

Matsushima, Jun ^{[3
]}

Furihata, Tomomi ^{[4
]}

Ikehara, Yuzuru ^{[5
]}

Ichikawa, Tomohiko ^{[2
]}

Anzai, Naohiko ^{[1
,6
]}

机构：

[1] Chiba Univ, Grad Sch Med, Dept Pharmacol, Chiba, Japan

[2] Chiba Univ, Grad Sch Med, Dept Urol, Chiba, Japan

[3] Dokkyo Med Univ Saitama, Med Ctr, Dept Pathol, Saitama, Japan

[4] Tokyo Univ Pharm & Life Sci, Dept Clin Pharm & Expt Therapeut, Tokyo, Japan

[5] Chiba Univ, Grad Sch Med, Dept Mol Tumor Pathol, Chiba, Japan

[6] Dokkyo Med Univ, Sch Med, Dept Pharmacol & Toxicol, Mibu, Tochigi, Japan

来源：

SCIENTIFIC REPORTS | 2019年 / 9卷 / 1期

基金：

日本学术振兴会;

关键词：

ACID TRANSPORTER 1; HYPOXIC MARKERS; INHIBITORS; MTORC1; JPH203;

D O I：

10.1038/s41598-019-53397-7

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Large neutral amino acid transporter 1 (LAT1, SLC7A5) is abundantly expressed in various types of cancer, and it has been thought to assist cancer progression through its activity for uptake of neutral amino acids. However, the roles of LAT1 in renal cell carcinoma (RCC) prognosis and treatment remain uncharacterized. Therefore, we first retrospectively examined the LAT1 expression profile and its associations with clinical factors in RCC tissues (n = 92). The results of immunohistochemistry showed that most of the tissues examined (92%) had cancer-associated LAT1 expression. Furthermore, the overall survival (OS) and progression-free survival (PFS) were shorter in patients with high LAT1 expression levels than in those with low LAT1 expression levels (P = 0.018 and 0.014, respectively), and these associations were further strengthened by the results of univariate and multivariate analyses. Next, we tested the effects of JPH203, which is a selective LAT1 inhibitor, on RCC-derived Caki-1 and ACHN cells. It was found that JPH203 inhibited the growth of these cell types in a dose-dependent manner. Moreover, JPH203 clearly suppressed their migration and invasion activities. Thus, our results show that LAT1 has a great potential to become not only a prognosis biomarker but also a therapeutic target in RCC clinical settings.

引用

页数：10

共 40 条

[11] Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): A literature review [J].

Gupta, Kiran ;

Miller, Jeffrey D. ;

Li, Jim Z. ;

Russel, Mason W. ;

Charbonneau, Claudie .

CANCER TREATMENT REVIEWS, 2008, 34 (03) :193-205

[12] Validation of Mammalian Target of Rapamycin Biomarker Panel in Patients with Clear Cell Renal Cell Carcinoma [J].

Haddad, Ahmed Q. ;

Kapur, Payal ;

Singla, Nirmish ;

Raman, Jay D. ;

Then, Matthew T. ;

Nuhn, Philipp ;

Buchner, Alexander ;

Bastian, Patrick ;

Seitz, Christian ;

Shariat, Shahrokh F. ;

Bensalah, Karim ;

Rioux-Leclercq, Nathalie ;

Sagalowsky, Arthur ;

Lotan, Yair ;

Margulis, Vitaly .

CANCER, 2015, 121 (01) :43-50

[13] The LAT1 inhibitor JPH203 reduces growth of thyroid carcinoma in a fully immunocompetent mouse model [J].

Hafliger, Pascal ;

Graff, Julien ;

Rubin, Matthias ;

Stooss, Amandine ;

Dettmer, Matthias S. ;

Altmann, Karl-Heinz ;

Gertsch, Jurg ;

Charles, Roch-Philippe .

JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH, 2018, 37

[14] External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study [J].

Heng, Daniel Y. C. ;

Xie, Wanling ;

Regan, Meredith M. ;

Harshman, Lauren C. ;

Bjarnason, Georg A. ;

Vaishampayan, Ulka N. ;

Mackenzie, Mary ;

Wood, Lori ;

Donskov, Frede ;

Tan, Min-Han ;

Rha, Sun-Young ;

Agarwal, Neeraj ;

Kollmannsberger, Christian ;

Rini, Brian I. ;

Choueiri, Toni K. .

LANCET ONCOLOGY, 2013, 14 (02) :141-148

[15] L-type amino acid transporter 1 (LAT1) expression in lymph node metastasis of gastric carcinoma: Its correlation with size of metastatic lesion and Ki-67 labeling [J].

Ichinoe, Masaaki ;

Yanagisawa, Nobuyuki ;

Mikami, Tetuo ;

Hana, Kiyomi ;

Nakada, Norihiro ;

Endou, Hitoshi ;

Okayasu, Isao ;

Murakumo, Yoshiki .

PATHOLOGY RESEARCH AND PRACTICE, 2015, 211 (07) :533-538

[16] FOXA1 Promotes Tumor Progression in Prostate Cancer via the Insulin-Like Growth Factor Binding Protein 3 Pathway [J].

Imamura, Yusuke ;

Sakamoto, Shinichi ;

Endo, Takumi ;

Utsumi, Takanobu ;

Fuse, Miki ;

Suyama, Takahito ;

Kawamura, Koji ;

Imamoto, Takashi ;

Yano, Kojiro ;

Uzawa, Katsuhiro ;

Nihei, Naoki ;

Suzuki, Hiroyoshi ;

Mizokami, Atsushi ;

Ueda, Takeshi ;

Seki, Naohiko ;

Tanzawa, Hideki ;

Ichikawa, Tomohiko .

PLOS ONE, 2012, 7 (08)

[17] Prognostic significance of L-type amino-acid transporter 1 expression in surgically resected pancreatic cancer [J].

Kaira, K. ;

Sunose, Y. ;

Arakawa, K. ;

Ogawa, T. ;

Sunaga, N. ;

Shimizu, K. ;

Tominaga, H. ;

Oriuchi, N. ;

Itoh, H. ;

Nagamori, S. ;

Kanai, Y. ;

Segawa, A. ;

Furuya, M. ;

Mori, M. ;

Oyama, T. ;

Takeyoshi, I. .

BRITISH JOURNAL OF CANCER, 2012, 107 (04) :632-638

[18] Expression of L-type amino acid transporter 1 (LAT1) in neuroendocrine tumors of the lung [J].

Kaira, Kyoichi ;

Oriuchi, Noboru ;

Imai, Hisao ;

Shimizu, Kimihiro ;

Yanagitani, Noriko ;

Sunaga, Noriaki ;

Hisada, Takeshi ;

Kawashima, Osamu ;

Iijima, Hironobu ;

Ishizuka, Tamotsu ;

Kanai, Yoshikatsu ;

Endou, Hitoshi ;

Nakajima, Takashi ;

Mori, Masatomo .

PATHOLOGY RESEARCH AND PRACTICE, 2008, 204 (08) :553-561

[19]

Kaira K, 2015, AM J TRANSL RES, V7, P1161

[20] Depolarized MUC1 Expression Is Closely Associated With Hypoxic Markers and Poor Outcome in Resected Non-Small Cell Lung Cancer [J].

Kaira, Kyoichi ;

Nakagawa, Kazuo ;

Ohde, Yasuhisa ;

Okumura, Takehiro ;

Takahashi, Toshiaki ;

Murakami, Haruyasu ;

Endo, Masahiro ;

Kondo, Haruhiko ;

Nakajima, Takashi ;

Yamamoto, Nobuyuki .

INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY, 2012, 20 (03) :223-232

← 1 2 3 4 →