Long non-coding RNA LINC00973 is a putative biomarker of colon cancer relapse


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Nikolai Lisitsyn1,Olga Zinovieva1,Evgenia Grineva1,Maria Prokofjeva1,Dmitry Karpov1,Andrei Zheltukhin1,George Krasnov1,Anastasiya Snezhkina1,Anna Kudryavtseva1,Peter Chumakov1,Tamara Mashkova1,Vladimir Prassolov1
1Engelhardt Institute of Molecular Biology

Abstract

Background

Early prediction of tumor relapse depends on identification of novel prognostic cancer biomarkers, which are suitable for monitoring of the response of various cancer types to the action of chemotherapeutic drugs.

Method

RNA-sequencing (RNA-Seq), RT-qPCR, and bioinformatics, combined with the study utilizing murine tumour xenograft model.

Results

We have found most significant (up to 100-fold) and consistent changes in the abundance of LINC00973 upon treatment of HT-29 and HCT-116 colon cancer cells with 5-fluorouracil, oxaliplatin, and irinotecan at different doses and durations, both in vitro and in vivo. Though the function of LINC00973 has not yet been determined, the RAID v2.0 database suggests that this RNA may form a complex with lncRNA CRNDE that is a part of the Polycomb repressive complex 2. This complex epigenetically silences DUSP/CDKN1A expression, promoting proliferation and suppressing apoptosis of colon cancer cells. Using CRISPR/Cas9 system we knocked out the LINC00973 encoding gene in HT-29 cells and found significant decrease in their proliferation and activation of apoptosis, as compared to intact controls. Besides, LINC00973 KO cells were much less resistant to chemotherapeutic drugs, which imply that overexpression of this RNA is a key event in the acquisition of chemoresistance by colon cancer cells. In accordance with these data, bioinformatics search revealed that expression of LINC00973 is drastically reduced in most types of carcinomas, but even small increase in LINC00973 abundance in most aggressive subtypes of colon cancer results in sharp increase in the probability of tumour relapse (hazard rate=1.34). Prognostic value of LINC00973 was also demonstrated for kidney and head and neck cancers.

Conclusion

LINC00973 is a perspective biomarker for prognosis of several cancer types. Further clinical studies are necessary in order to determine, if measurement of the LINC00973 abundance throughout the course of neoadjuvant therapy might be useful for the reliable prediction of colon cancer relapse.