PMID- 33456563
OWN - NLM
STAT- MEDLINE
DCOM- 20210727
LR  - 20231110
IS  - 1838-7640 (Electronic)
IS  - 1838-7640 (Linking)
VI  - 11
IP  - 6
DP  - 2021
TI  - CXCL12-mediated HOXB5 overexpression facilitates Colorectal Cancer metastasis 
      through transactivating CXCR4 and ITGB3.
PG  - 2612-2633
LID - 10.7150/thno.52199 [doi]
AB  - Background: Metastasis is the major reason for the high mortality of colorectal 
      cancer (CRC). However, the molecular mechanism underlying CRC metastasis remains 
      unclear. Here, we report a novel role of homeobox B5 (HOXB5), a member of the HOX 
      family, in promoting CRC metastasis. Method: The expression of HOXB5 and its 
      target genes were examined by immunohistochemistry in human CRC. Chromatin 
      immunoprecipitation and luciferase reporter assays were performed to measure the 
      transcriptional regulation of target genes by HOXB5. The metastatic capacities of 
      CRC cells were evaluated by in vivo lung and liver metastatic models. Results: 
      The elevated expression of HOXB5 was positively correlated with distant 
      metastasis, higher AJCC stage, and poor prognosis in CRC patients. HOXB5 
      expression was an independent and significant risk factor for the recurrence and 
      survival in CRC patients. Overexpression of HOXB5 promoted CRC metastasis by 
      transactivating metastatic related genes, C-X-C motif chemokine receptor 4 
      (CXCR4) and integrin subunit beta 3 (ITGB3). C-X-C motif chemokine ligand 12 
      (CXCL12), which is the ligand of CXCR4, upregulated HOXB5 expression through the 
      extracellular regulated protein kinase (ERK)/ETS proto-oncogene 1, transcription 
      factor (ETS1) pathway. The knockdown of HOXB5 decreased CXCL12-enhanced CRC 
      metastasis. Furthermore, AMD3100, a specific CXCR4 inhibitor, significantly 
      suppressed HOXB5-mediated CRC metastasis. HOXB5 expression was positively 
      correlated with CXCR4 and ITGB3 expression in human CRC tissues, and patients 
      with positive co-expression of HOXB5/CXCR4, or HOXB5/ITGB3 exhibited the worst 
      prognosis. Conclusion: Our study implicates HOXB5 as a prognostic biomarker in 
      CRC, and defines a CXCL12-HOXB5-CXCR4 positive feedback loop that plays an 
      important role in promoting CRC metastasis.
CI  - (c) The author(s).
FAU - Feng, Weibo
AU  - Feng W
AD  - State key Laboratory of Cancer Biology, National Clinical Research Center for 
      Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military 
      Medical University, Xi'an 710032, Shaanxi Province, China.
FAU - Huang, Wenjie
AU  - Huang W
AD  - Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, 
      Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of 
      Tongji Medical College, Huazhong University of Science and Technology, Wuhan 
      430030, Hubei Province, China.
AD  - Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong 
      University of Science and Technology; Clinical Medicine Research Center for 
      Hepatic Surgery of Hubei Province; Key Laboratory of Organ Transplantation, 
      Ministry of Education and Ministry of Public Health, Wuhan, Hubei, 430030, China.
FAU - Chen, Jie
AU  - Chen J
AD  - State key Laboratory of Cancer Biology, National Clinical Research Center for 
      Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military 
      Medical University, Xi'an 710032, Shaanxi Province, China.
FAU - Qiao, Chenyang
AU  - Qiao C
AD  - State key Laboratory of Cancer Biology, National Clinical Research Center for 
      Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military 
      Medical University, Xi'an 710032, Shaanxi Province, China.
FAU - Liu, Danfei
AU  - Liu D
AD  - Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, 
      Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of 
      Tongji Medical College, Huazhong University of Science and Technology, Wuhan 
      430030, Hubei Province, China.
FAU - Ji, Xiaoyu
AU  - Ji X
AD  - Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, 
      Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of 
      Tongji Medical College, Huazhong University of Science and Technology, Wuhan 
      430030, Hubei Province, China.
FAU - Xie, Meng
AU  - Xie M
AD  - Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, 
      Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of 
      Tongji Medical College, Huazhong University of Science and Technology, Wuhan 
      430030, Hubei Province, China.
FAU - Zhang, Tongyue
AU  - Zhang T
AD  - Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, 
      Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of 
      Tongji Medical College, Huazhong University of Science and Technology, Wuhan 
      430030, Hubei Province, China.
FAU - Wang, Yijun
AU  - Wang Y
AD  - Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, 
      Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of 
      Tongji Medical College, Huazhong University of Science and Technology, Wuhan 
      430030, Hubei Province, China.
FAU - Sun, Mengyu
AU  - Sun M
AD  - Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, 
      Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of 
      Tongji Medical College, Huazhong University of Science and Technology, Wuhan 
      430030, Hubei Province, China.
FAU - Tian, Dean
AU  - Tian D
AD  - Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, 
      Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of 
      Tongji Medical College, Huazhong University of Science and Technology, Wuhan 
      430030, Hubei Province, China.
FAU - Fan, Daiming
AU  - Fan D
AD  - State key Laboratory of Cancer Biology, National Clinical Research Center for 
      Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military 
      Medical University, Xi'an 710032, Shaanxi Province, China.
FAU - Nie, Yongzhan
AU  - Nie Y
AD  - State key Laboratory of Cancer Biology, National Clinical Research Center for 
      Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military 
      Medical University, Xi'an 710032, Shaanxi Province, China.
FAU - Wu, Kaichun
AU  - Wu K
AD  - State key Laboratory of Cancer Biology, National Clinical Research Center for 
      Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military 
      Medical University, Xi'an 710032, Shaanxi Province, China.
FAU - Xia, Limin
AU  - Xia L
AD  - State key Laboratory of Cancer Biology, National Clinical Research Center for 
      Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military 
      Medical University, Xi'an 710032, Shaanxi Province, China.
AD  - Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, 
      Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of 
      Tongji Medical College, Huazhong University of Science and Technology, Wuhan 
      430030, Hubei Province, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210101
PL  - Australia
TA  - Theranostics
JT  - Theranostics
JID - 101552395
RN  - 0 (Benzylamines)
RN  - 0 (CXCL12 protein, human)
RN  - 0 (CXCR4 protein, human)
RN  - 0 (Chemokine CXCL12)
RN  - 0 (Cyclams)
RN  - 0 (HOXB5 protein, human)
RN  - 0 (Homeodomain Proteins)
RN  - 0 (ITGB3 protein, human)
RN  - 0 (Integrin beta3)
RN  - 0 (MAS1 protein, human)
RN  - 0 (Proto-Oncogene Mas)
RN  - 0 (Receptors, CXCR4)
RN  - S915P5499N (plerixafor)
SB  - IM
MH  - Aged
MH  - Animals
MH  - Benzylamines/pharmacology
MH  - Caco-2 Cells
MH  - Cell Line, Tumor
MH  - Cell Movement/drug effects/genetics
MH  - Chemokine CXCL12/*genetics
MH  - Colorectal Neoplasms/drug therapy/*genetics/pathology
MH  - Cyclams/pharmacology
MH  - Female
MH  - Gene Expression Regulation, Neoplastic/drug effects/genetics
MH  - Homeodomain Proteins/*genetics
MH  - Humans
MH  - Integrin beta3/*genetics
MH  - Liver Neoplasms/genetics/pathology
MH  - Lung Neoplasms/genetics/pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Neoplasm Recurrence, Local/drug therapy/genetics/pathology
MH  - Proto-Oncogene Mas
MH  - Receptors, CXCR4/*genetics
MH  - Signal Transduction/drug effects/genetics
MH  - Transcriptional Activation/drug effects/*genetics
MH  - Up-Regulation/drug effects/genetics
PMC - PMC7806482
OTO - NOTNLM
OT  - AMD3100
OT  - C-X-C motif chemokine receptor 4
OT  - colorectal cancer
OT  - homeobox B5
OT  - metastasis
COIS- Competing Interests: The authors have declared that no competing interest exists.
EDAT- 2021/01/19 06:00
MHDA- 2021/07/28 06:00
PMCR- 2021/01/01
CRDT- 2021/01/18 05:29
PHST- 2020/08/20 00:00 [received]
PHST- 2020/12/05 00:00 [accepted]
PHST- 2021/01/18 05:29 [entrez]
PHST- 2021/01/19 06:00 [pubmed]
PHST- 2021/07/28 06:00 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - thnov11p2612 [pii]
AID - 10.7150/thno.52199 [doi]
PST - epublish
SO  - Theranostics. 2021 Jan 1;11(6):2612-2633. doi: 10.7150/thno.52199. eCollection 
      2021.