Differential Expression of CHL1 Gene during Development of Major Human Cancers

Vera N Senchenko,Ekaterina A Anedchenko,Tatiana T Kondratieva,Eugene R Zabarovsky,Alexey A Dmitriev,Eleonora A Braga,Michael I Lerman,Anna V Kudryavtseva,Irina V Pronina,George S Krasnov,Sergey V Ivanov,Chad Creighton

doi:10.1371/journal.pone.0015612

Abstract

Background CHL1 gene (also known as CALL) on 3p26.3 encodes a one-pass trans-membrane cell adhesion molecule (CAM). Previously CAMs of this type, including L1, were shown to be involved in cancer growth and metastasis.Methodology/Principal FindingsWe used Clontech Cancer Profiling Arrays (19 different types of cancers, 395 samples) to analyze expression of the CHL1 gene. The results were further validated by RT-qPCR for breast, renal and lung cancer. Cancer Profiling Arrays revealed differential expression of the gene: down-regulation/silencing in a majority of primary tumors and up-regulation associated with invasive/metastatic growth. Frequent down-regulation (>40% of cases) was detected in 11 types of cancer (breast, kidney, rectum, colon, thyroid, stomach, skin, small intestine, bladder, vulva and pancreatic cancer) and frequent up-regulation (>40% of cases) – in 5 types (lung, ovary, uterus, liver and trachea) of cancer. Using real-time quantitative PCR (RT-qPCR) we found that CHL1 expression was decreased in 61% of breast, 60% of lung, 87% of clear cell and 89% papillary renal cancer specimens (P<0.03 for all the cases). There was a higher frequency of CHL1 mRNA decrease in lung squamous cell carcinoma compared to adenocarcinoma (81% vs. 38%, P = 0.02) without association with tumor progression.Conclusions/SignificanceOur results suggested that CHL1 is involved in the development of different human cancers. Initially, during the primary tumor growth CHL1 could act as a putative tumor suppressor and is silenced to facilitate in situ tumor growth for 11 cancer types. We also suggested that re-expression of the gene on the edge of tumor mass might promote local invasive growth and enable further metastatic spread in ovary, colon and breast cancer. Our data also supported the role of CHL1 as a potentially novel specific biomarker in the early pathogenesis of two major histological types of renal cancer.

Highlights

Cancer-associated genes fall into two main categories: cancercausing genes that drive malignant transformation and maintain tumor growth, and cancer progression genes that orchestrate local invasion and further spread of metastatic cells and growth of distant metastases [1,2,3]
Variable expression was seen in many tumors; it was especially high in a melanoma cell line G361
Note: *P – p-parameter, characterized the difference between group with metastases and group without metastases, taking into account 3 possible events: decrease, increase and retention of mRNA level in tumor samples comparing to adjusted normal samples

Summary

Introduction

Cancer-associated genes fall into two main categories: cancercausing genes that drive malignant transformation and maintain tumor growth, and cancer progression genes that orchestrate local invasion and further spread of metastatic cells and growth of distant metastases [1,2,3]. Several CAMs including L1 were shown to be involved in cancer growth and metastasis [9,10]. CHL1 is located at 3p26, a region that is shown to harbor a candidate for prostate cancer susceptibility in Finnish prostate cancer families, no mutations were detected in the coding part of the gene [11]. These reports suggest that CHL1 plays a role in cancer development [12], in neuronal activities. CHL1 gene ( known as CALL) on 3p26.3 encodes a one-pass trans-membrane cell adhesion molecule (CAM). CAMs of this type, including L1, were shown to be involved in cancer growth and metastasis

Methods

Results

Conclusion