Specific Gene Emerges as Potential Cervical Cancer Prognostic Marker, Therapeutic Target

Specific Gene Emerges as Potential Cervical Cancer Prognostic Marker, Therapeutic Target

A study assessing genetic variations in cervical cancer tissues identified the gene CLDN1 (Claudin 1 protein) as playing a significant role in cervical cancer progression through its ability to promote cancer cell survival and metastasis.

The study, “CLDN1 expression in cervical cancer cells is related to tumor invasion and metastasis” published in Oncotarget, suggests that CLDN1 may be a potential therapeutic target to treat patients with cervical cancer.

Since infection with human papillomavirus (HPV) is not the sole cause of cervical cancer in women, it is necessary to identify additional genetic abnormalities that can contribute to tumor progression.

One way to detect such genetic abnormalities is through a technique called array comparative genomic hybridization (array CGH), which enables the detection of gain and loss of chromosomal regions. When regions of our DNA are either amplified or lost, levels of gene expression change, and this can be critical for disease progression.

To shed some light on the genetic mechanisms involved in cervical cancer, researchers used array CGH to identify genes commonly altered in cervical squamous cell carcinoma, and whose changes are correlated to the progression of the disease and possibly its transition from a premalignant state to a cancerous one.

Over 50 genes were found to be amplified after performing array CGH on 10 cervical cancer samples. In addition, nearly 80 genes were frequently absent in the examined samples.

Of these, the researchers selected 16 genes to be further validated at each level of gene expression. Those included genes that were amplified in more than 30 percent of cases, and genes that were lost in more than 60 percent of cases.

Gene expression involves two main steps: expression of mRNA from the DNA, and translation of mRNA into a functioning protein. One gene in particular, CLDN1, was found to be amplified not at the DNA level, but its mRNA and protein levels were increased when compared to normal tissue.

Claudin proteins, including Claudin 1, are found at the cell membrane and are critical to maintain tight boundaries between cells. Several members of the claudin family of proteins have been found at high levels in different cancers, including breast and prostate cancers.

In the present study, investigators found that Claudin 1 protein levels correlated with increased metastasis to the lymph nodes as well as with cervical cancer’s aggressiveness.

To understand the role of CLDN1 in promoting cervical cancer progression, the researchers turned to cell line and mouse models. They found that in a culture dish, high expression of CLDN1 rendered cells more resistant to cell death.

In addition, CLDN1 made cells more invasive, increasing the likelihood of metastasis. Cancer cells gain the ability to invade surrounding tissue and migrate to distant sites through a process called the epithelial-mesenchymal transition (EMT). In this process, cells change their shape by altering the expression of specific genes such as E-cadherin and vimentin. Not surprisingly, the researchers found that cells with high levels of CLDN1 seemed to have undergone EMT, showing reduced expression of E-cadherin and increased vimentin.

Mouse models supported these results. When implanted into mice, cells with high CLDN1 expression developed larger tumors with more metastatic lung lesions compared to cells with reduced CLDN1 expression.

The combination of these results makes CLDN1 an interesting gene to study further. “CLDN1 may be a potential prognostic marker and a candidate cell surface therapeutic target in cervical cancer,” the authors wrote.

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