Keneng Chen, M.D., PhD, RCSF Luyan Shen, M.D., PhD 2015/4/28

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HOXC6 and HOXC8 are potentially novel prognosis predictors of esophageal squamous cell carcinoma Keneng Chen, M.D., PhD, RCSF Luyan Shen, M.D., PhD 2015/4/28 Department of Thoracic Surgery I, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Cancer Hospital, Peking University School of Oncology, Beijing, China

No potential conflicts of interest were disclosed

Several issues with the clinical practice of ESCC remain unsolved prognosis goal Chemo response The morbidity and mortality remains high 01 long-term survival remains unsatisfied 02 模板来自于 http://docer.wps.cn Lack of reports with long-term follow-up data from prospective database 03 Lack of efficient biomarkers for helping to guide the clinical practice 04 3

Why we choose HOX genes ? There is some similarity between embryogenesis and tumorigenesis 01 AFP in liver cancer and CEA in colorectal cancer 02 HOX gene family regulates embryogenesis 03 HOX genes are deregulated in hematologic malignancy and many solid tumors 04

Regional expression of transcription factors in the developing gut Yuasa Y. Nat Rev Cancer. 2003.

potential biomakers Expression of 11 HOX genes is deregulated in ESCC HOX genes were abnormally expressed in ESCC (n=36) Gene Positive cases in ESCC(%) Positive cases in noncancerous mucosa(%) HOXA10 3(8.3) 0(0) HOXA13 27(75) HOXB7 21(58.3) HOXC4 12(33.3) HOXC8 15(41.7) HOXD9 6(16.7) HOXD10 HOXD13 HOXA7 30(83.3) HOXA9 24(66.7) 9(25) HOXC6 We detected the expression pattern of 39 HOX genes in ESCC tissue and noncancerous mucosa by using RT-PCR, and then found that eight HOX genes were expressed only in some ESCC tissues but in any of the noncancerous mucosa samples. Spectically, the positive rate of HOXA13 was the highest, in 36 cases of ESCC samples, 27 presented positive. potential biomakers Chen KN, et al. Clin Cancer Res. 2005.

Study design and work flow diagram FFPE tissue specimen IHC for HOXC6、HOXC8 protein detection FFPE tissue specimen Prognosis S Group (138 ) NC+S Group (136) S+AC Group (148) Lentivirus infection CCK8 Assay Proliferation Annexin v/PI Cell cycle & Apoptosis KYSE-450 Soft agar colony formation assay Ability of colony formation Knockdown of HOXC6/HOXC8 Tumor formation in nude mice Ability of tumorigenesis

Staining of IHC

Survival analysis in naive subgroup Median survival，mo(95%CI) Surgery only p = 0.070 p = 0.005 The association of HOXC6/HOXC8 expression with overall survival in naive subgroup (n=138) Item No. (%) Median survival，mo(95%CI) 5-y survival (%) p HOXC6 Low expression 83(60.1) 70.1(34.2-105.9) 51.5 0.070 High expression 55(39.9) 35.0(23.2-46.8) 32.9 HOXC8 85(61.6) 110.3(35.5-185.3) 51.9 0.005 53(38.4) 30.3(17.7-42.9) 30.6 Du YB, et al. J Surg Res, 2014.

Survival analysis in neoadjuvant chemotherapy subgroup NC+S p = 0.002 p = 0.004 The association of HOXC6/HOXC8 expression with overall survival in neoadjuvant subgroup (n=136) Item No.(%) Median survival mo(95%CI) 5-y survival (%) p HOXC6 Low expression 31(22.8) 82.7(-) 60 0.002 High expression 105(77.2) 27.8(16.7-38.8) 33 HOXC8 73(53.7) 110.3(-) 49.9 0.004 63(46.3) 21.2(16.5-38.9) 25 Du YB, et al. J Surg Res, 2014.

Survival analysis in adjuvant chemotherapy subgroup S+AC p = 0.002 p = 0.001 The association of HOXC6/HOXC8 expression with overall survival in neoadjuvant subgroup (n=148) Item No.(%) Median survival mo(95%CI) 5-y survival (%) p HOXC6 Low expression 81(54.7) 61.0(21.8-112.2) 53.8 0.002 High expression 67(45.3) 33.4(20.5-46.3) 30.3 HOXC8 99(66.9) 62.3(41.5-83.0) 53.0 0.001 49(33.1) 31.3(16.9-45.8) 21.7

HOXC6/HOXC8 Knock-down at mRNA and Protein level

Tumor growth in nude mice Down-regulation affects cell proliferation in vitro & in vivo CCK8 assay Tumor growth in nude mice shNC shHOXC6 shHOXC8 Soft agar Colony formation HOXC6(-) HOXC8(-) Control

Down-regulation affects cell apoptosis in vitro Apoptosis rate variation when HOXC6 or HOXC8 was knock-down Apoptosis rate（%） ShHOXC6 32.8±0.29* ShHOXC8 36.1±0.35* ShNC 12.7±0.31 * p ＜ 0.050

Down-regulation affects cell cycle in vitro HOXC6(-) HOXC8(-) Control Knockdown of HOXC6 and HOXC8 Affects the Cell Cycle G2+S(%) G1(%) shHOXC6 45.38±2.29* 54.62±2.29* shHOXC8 28.04±3.1* 71.9±3.1* shNC 64.87±3.17 35.1±3.17 * p ＜ 0.050

Conclusion HOXC6, HOXC8 might be a biomarker for evaluating prognosis and chemo response of ESCC 01 Down-regulation of HOXC6/HOXC8 inhibited the cancer cell progression 02

Acknowledgment Dr. Chen’s LAB: Yabing Du Bin Dong Wanpu Yan Liang Dai Xiaozheng Kang Zhen Liang Hongchao Xiong

HOX genes present the expression pattern of temporal and spatial colinearity A13 A11 A10 A9 B9 A6 A5 A4 A3 A2 A1 7p15.3 B13 B9 B8 B7 B6 B5 B4 B3 B2 B1 17p21.3 C13 C12 C11 C10 C9 C8 C6 C5 C4 12q13.3 D13 D12 D11 D10 D9 D8 D4 D3 D1 As we know, many molecular pathways underlying carcinogenesis represents aberrations of normal processes that control embyogenesis. There are many examples, the abnormal expression of these genes which regulate growth and development were implicated in carcinogenesis. Among these examples are HOX genes, which encode transcript regulatory proteins that are widely expressed in development and aberrantly expressed in cancers. There are 39 HOX genes organised in four genomic clusters,each localised on a different chromosome (HOX A HOXB, HOXC, and HOX D) and comprising from 9 to 11 genes arranged in a homologous sequence organisation. During mammalian development, according to the rules of temporal and spatial colinearity, with 3' Hox genes expressed early in development and controlling anterior regions, followed by progressively more 5' genes expressed later in development and controlling more posterior regions. For example, HOXA13 located at 5' terminal, primarily control the development of lumbo-scaral region, including In particular, 3' Hox genes in groups 1 to 4 primarily control the development of the branchial area and the rhombencephalon, the embryonic region corresponding to the hindbrain. Central Hox genes in groups 5 to 8 control the thoracic portion of the body, whereas 5' Hox genes in groups 9 to 13 control the lumbo-sacral region, including hindgut, urinary system and genitalia. 2q31 13 12 11 10 9 8 7 6 5 4 3 2 1 lumbo-sacral thoracic cervical Posterior Late 5' 3' Anterior Early Schematics representation of four HOX loci Cillo C, et al. J cell physiol, 2001

HOXC6/HOXC8 expression was related with TNM stage Association between HOXC6 or HOXC8 expression and clinical characteristics (n=274) Clinicopathologic Characteristics HOXC6 expression No.(%) P HOXC8 expression No.(%) High Low Age ≦60 74(62.7) 44(37.3) 0.219 53(44.9) 65(55.1) 0.309 ＞60 87(55.0) 71(45.0) 63(39.9) 95(60.1) Sex Male 121(59.0) 84(41.0) 0.891 88(42.9) 117(57.1) 0.608 Female 40(56.3) 31(43.7) 28(39.4) 43(60.6) G stage G1 10(41.7) 14(58.3) 0.010 8(33.3) 16(66.7) 0.222 G2 25(39.0) 39(61.0) 29(45.3) 35(54.7) G3 20(40.0) 30(60.0) 16(32.0) 34(68.0) Tumor location(L) L0 15(62.5) 9(37.5) 0.101 0.524 L1 38(67.9) 18(32.1) 26(46.4) 30(53.6) L2 75(59.1) 52(40.9) 57(44.9) 70(55.1) L3 30(46.2) 35(53.8) 23(35.4) 42(64.6) Tumor invasion(T) T1 33(47.1) 37(52.9) 0.011 19(27.1) 51(72.9) <0.001 T2 33(50.0) 22(34.9) 41(65.1) T3 68(63.0) 40(37.0) 52(48.1) 56(51.9) T4 26(78.8) 7(21.2) 23(69.7) 10(30.3) Lymph node metastasis (N) N0 96(53.9) 82(46.1) 0.031 65(36.5) 113(63.5) 0.004 N1 33(58.9) 23(41.1) 32(57.1) 24(42.9) N2 20(71.4) 8(28.6) 10(35.7) 18(64.3) N3 11(91.7) 1(8.30) 9(75.0) 3(25.0) TNMG stage I 79(45.7) 94(54.3) 59(34.1) 114(65.9) 0.001 II 41(73.2) 15(26.8) 28(50.0) III 41(87.2) 6(12.8) 29(61.7) 18(38.3)

Tumor Regression Grade (TRG) NC+S The association of HOXC6 and HOXC8 expression with TRG (n=136) HOXC6 expression No.(%) p HOXC8 expression No.(%) Low High TRG TRG1/2 15(48.4) 27(30.9） 0.016 35(47.9) 7(11.1) <0.001 TRG3/4 16(51.6) 78(69.1) 38(52.1) 56(88.9) Du YB, et al. J Surg Res, 2014.