LOH12CR1 is a Novel Tumor Suppressor Inhibiting Tumor Growth Through Deregulation of G1/S Checkpoint in Human Colorectal Carcinoma

H Huang; H Shen; Y Wang; X Wang; Q Chen; Y Wang; H Yan; Z Liu; X Shi

doi:10.2174/1566524018666180608084005

LOH12CR1 is a Novel Tumor Suppressor Inhibiting Tumor Growth Through Deregulation of G1/S Checkpoint in Human Colorectal Carcinoma

Curr Mol Med. 2018;18(1):25-35. doi: 10.2174/1566524018666180608084005.

Authors

H Huang¹, H Shen^{1

2}, Y Wang^{1

3}, X Wang⁴, Q Chen^{1

3}, Y Wang^{1

3}, H Yan^{1

3}, Z Liu⁵, X Shi¹

Affiliations

¹ Department of Medical Genetics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
² Center for Medical Research, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
³ Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
⁴ Department of Gastroenterology of Xi-Jing Hospital, China.
⁵ College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China.

PMID: 29879888
DOI: 10.2174/1566524018666180608084005

Abstract

Background: Loss of heterozygosity (LOH) of 12p12-13 has been frequently found in various types of cancer. LOH12CR1 is one of the seven critical genes located within the 12p12-13 region. The protein encoded by LOH12CR1 is involved in the function of lysosomes and its other functions are still unclear.

Objective: The aim of this study is to investigate the potential roles of LOH12CR1 in the development of colorectal cancer.

Methods: A total of 174 colorectal cancer tissues were used to examine the protein level of LOH12CR1 by immunohistochemistry staining. The correlation between LOH12CR1 expression and the patient prognosis was further investigated through retrospective study. The tumor suppression capacity was examined by knockdown or overexpression of LOH12CR1 in four colorectal cancer cell lines and one normal cell line.

Results: Significant decrease of LOH12CR1 protein was observed in colorectal cancerous tissues (P<0.001). Knockdown of LOH12CR1 promoted colorectal cancer cell proliferation, colony formation, and accelerated G1/S cell cycle transition through downregulation of p16^INK4a and p21^WAF1/CIP1, while ectopic expression of LOH12CR1 displayed the opposite effects. The protein level of LOH12CR1 was well correlated with the expression of p16^INK4a and p21^WAF1/CIP1. Most importantly, the protein level of LOH12CR1 negatively correlated with clinical prognosis of colorectal carcinomas.

Conclusion: The present results suggest that LOH12CR1 might function as a tumor suppressor. Thus, loss of function of LOH12CR1 might be a potential driver in the development of colorectal carcinoma. Detection of LOH12CR1 could be used as a method for diagnosis and therapeutic assessment of patients with colorectal cancer.

Keywords: G1/S arrest; LOH12CR1; cell cycle; colorectal cancer; p16; p21; tumor suppressor..

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Caco-2 Cells
Colorectal Neoplasms / genetics
Colorectal Neoplasms / metabolism*
Colorectal Neoplasms / pathology
Cyclin-Dependent Kinase Inhibitor p16 / genetics
Cyclin-Dependent Kinase Inhibitor p16 / metabolism
Cyclin-Dependent Kinase Inhibitor p21 / genetics
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
G1 Phase Cell Cycle Checkpoints*
Gene Knockdown Techniques
HCT116 Cells
Humans
S Phase Cell Cycle Checkpoints*
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism*

Substances

CDKN1A protein, human
CDKN2A protein, human
Cyclin-Dependent Kinase Inhibitor p16
Cyclin-Dependent Kinase Inhibitor p21
Tumor Suppressor Proteins