α-Actinin-4 regulates cancer stem cell properties and chemoresistance in cervical cancer

Cancer stem cells (CSCs) is the subpopulation of cells represents the critical subset within the tumour mass in perpetuating the tumour, even after what seems to be effective therapy and leads to tumour aggression. They have several functions including differentiation, self-renewal and drug resistance, they also play an essential role in tumor initiation. Globally, human cervical cancer is the third most common type of cancer and the fourth cause of death related to female cancer. There are several causes of cervical cancer but the most common cause is human papilloma virus infection. Despite the development of many drugs to treat cervical cancer, the treatments most times lead to chemoresistance resulting in relapse. Therefore, in developing drugs to treat cervical cancer, it is important to understand the molecular mechanism of chemoresistance. α-Actinin (ACTN) is a protein that binds to actin and in humans, 4 isoforms have been established; ACTN1, ACTN2, ACTN3 and ACTN4. Studies have shown that ACTN4 is linked to malignant phenotypes and metastatic abilities in some cancers such as ovarian, colorectal and breast cancers. In ovarian cancer, ACTN4 is overexpressed and this is associated with tumor chemoresistance. Researchers are yet to identify the role ACTN4 plays in cervical cancer’s cancer cell stemness.

To demonstrate the role ACTN4 plays in the regulation of CSC properties and chemoresistance in cervical cancer, Korea University researchers: Dr. Jaeyeon Jung together with Dr. Suhyun Kim, Dr. Hyoung-Tae An and Dr. Jesang Ko showed an increase in the expression of ACTN4 mRNA in cancerous cervices compared to normal cervices. The research work is published in the Journal Carcinogenesis.

The authors observed that sphere formation in cervical cancer was suppressed by the knockdown of ACTN4. This is an indication that ACTN4 has a crucial function in the formation of CSC in cervical cancer. In addition, it revealed that the ability of cervical cancer cells to self-renew is alleviated by ACTN4 knockdown. They also noticed that the expression of CSC marker in cervical cancer is regulated by ACTN4. Specifically, results from real-time PCR showed that ACTN4 knockdown resulted in an increase in CDH1 and KLF4 mRNA levels and a decrease in CSC marker ABCG2 and BMI1 mRNA levels

Knockdown of ACTN4 was also found to inhibit the proliferation of CSC and epitheliaα–mesenchymal transition thereby promoting CSC characteristics. A reduction in secondary spheroid cell growth was observed following ACTN4 knockdown, this manifested as a decrease in the sizes of spheroid and expression of E-cadherin. CSCs with ACTN4 knockdown were found to be susceptible to anticancer drugs. This implies that ACTN4 aids chemoresistance to different anticancer drugs thereby giving cervical cancer cells a survival advantage to. In vivo, ACTN4-knockdown CSCs were noticed to form fewer tumors.

In summary, the research team have been able to demonstrate that ACTN4 controls the characteristics of CSCs and adds to chemoresistance in cervical cancer. Their findings show that ACTN4 has the potential to be used in the development of therapeutic agents targeted at regulating tumor growth and metastasis in cervical cancer with chemoresistance