Triple-negative breast cancer & involvement of ncRNAs

Shrestha Dutta, Amity University Kolkata

A quick rising pattern has been seen in the frequency of breast cancer (BC) with more than 1 million cases diagnosed every year. As per the molecular properties of HER-2, estrogen receptor (ER), ki-67, and progesterone receptor (PR), BC can be further be divided into assorted subtypes, for example, HER-2 overexpression, Lumina A, Lumina B, ‘normal like’ breast tumors and basal-like tumors. As characterized, triple-negative breast cancer (TNBC) is a tumor which is negative for HER-2, ER and PR. Presently, surgical resection and chemotherapy are the major foundational treatments for patients with TNBC because of the absence of effective biomarker. It was acknowledged that non-coding RNAs (ncRNAs) are the basic components in the regulation of expression of genes, thereby applying functions on tumor or non-tumor cell aggregates.

Long non-coding RNAs (lncRNAs) are commonly regarded as genomic transcripts surpassing 200 nucleotides. It has been suggested by different scientists that lncRNAs are related to molecular components fundamental for formation of malignant cells and can be utilized as promising biomarkers and therapeutic targets for malignancies. LncRNAs are involved in tumorigenesis and movement of malignancies by means of different mechanisms. Critically, lncRNA can work as a contending endogenous RNA (ceRNA) to increase regulation of mRNA expression by sponging microRNA (miRNA). Additionally, lncRNAs can control tumor initiation by combining with RNA-binding proteins (RBPs) to keep up with the stability of mRNA.

Method followed in the study:

Expression of PITPNA-AS1 in TNBC tissues and cells was demonstrated by RT-qPCR. TNBC cell longevity, multiplication, movement, and intrusion were studied with CCK-8, formation of colonies, healing of wounds, and transwell tests. Cell apoptosis was assessed by flow cytometry. EMT-related marker expression was recognized by western blotting. The molecular technique of PITPNA-AS1 was investigated by RNA pull down, luciferase reporter, RIP and ChIP test.

Results:

PITPNA-AS1 demonstrates a high level of expressions in TNBC tissues and cells. PITPNA-AS1 knockdown reduces viability of TNBC cells, expansion, relocation, intrusion in vitro and inhibited xenograft tumor development in mice. Mechanistically, PITPNA-AS1 increases regulation of expression of SIK2 by sponging miR-520d-5p and enrolling DDX54 protein. The after effects of the rescue assay proposed that the inhibitive impacts of hushed PITPNA-AS1 on TNBC cell measures are partially safeguarded by overexpressing SIK2 or blend of miR-520d-5p hindrance and DDX54 overexpression. All the more significantly, scientists tracked down that the upregulation of PITPNA-AS1 in TNBC cells was credited to transcription factor MYBL2 (v-myb myeloblastosis viral oncogene homolog (avian)-like 2).

Significance of the study:

Long non-coding RNAs (lncRNAs) have drawn much attention due to its regulatory role in occurrence and growth of tumors, including triple-negative breast cancer (TNBC). LncRNA PITPNA antisense RNA 1 (PITPNA-AS1) has been found in certain malignancies, while its function and molecular mechanism in TNBC is still not clear. Research demonstrates that lncRNAs are involved in the occurrence and growth of different human cancers by sponging miRNA or recruiting RBPs. The critical roles of abnormally expressed lncRNAs have been observed in TNBC growth. Studies also showed that expression of  PITPNA-AS1 in TNBC cells is higher than in control tissue and cells, and mostly found in the cytoplasm of TNBC cells. When PITPNA-AS1 is activated by MYBL2, it plays an oncogenic role in TNBC through increased regulation of SIK2 (Salt inducible kinase 2).

Also read: Natural killer cells: Defence against self-destruction

Reference:

1. Liu, B., Yao, P., Xiao, F., Guo, J., Wu, L., & Yang, Y. (2021). MYBL2-induced PITPNA-AS1 upregulates SIK2 to exert oncogenic function in triple-negative breast cancer through miR-520d-5p and DDX54. Journal of Translational Medicine, 19(1), 333. https://doi.org/10.1186/s12967-021-02956-6

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