Rukan Huq

Introduction: HCC is the most common cancer of the liver and is a leading cause of cancer mortality worldwide with increasing incidence.^1,2 Chronic liver disease, cirrhosis, and Hepatitis B/C viruses are strongly implicated in HCC development.² HCC has a poor prognosis with no definitive cure since radiation/chemotherapies and drugs have limited capacities in improvement and liver transplantation is not always an accessible option.³ ITGB1 is a cell surface receptor associated with liver regeneration that plays a crucial role in HCC progression and metastasis, so targeting ITGB1 may be a new avenue for HCC treatment.⁴ Methods: Two studies used tissues from HCC patients to compare linc-ITGB1 expression levels to non-cancerous tissues. A shRNA against linc-ITGB1 was synthesized to knockdown expression of linc-ITGB1 in HCC cells.^5,6 The effects on ability of HCC cell proliferation, migration, and invasion were analyzed. Another study utilized multicellular spheroids of human HCC cell lines and monolayer cells and exposed them to 5-fuluoruracil and cisplatin, and then ITGB1 was targeted with an inhibitory antibody.⁷ The effects on cell proliferation and apoptosis induction were observed. One more study induced ITGB1 overexpression through an adenovirus-carrying ITGB1 gene expression cassette, while silencing was implemented through a shRNA.⁸ Xenograft mouse models were established with ITGB1+ or ITGB1- HCC cells, and evaluated for protein expression and cell viability. Results: ITGB1 levels in HCC tissues was significantly higher compared to normal tissues in all studies.^5-8 With linc-ITGB1 knockdown, cell cycle analysis demonstrated cells amassing in the G0/G1 phase with cell cycle arrestment and significant decrease in migration and invasion.⁵ Linc-ITGB1 knockdown showed ZEB1 expression inhibition which suppressed EMT which is important in metastasis.⁶ Multicellular spheroids had higher levels of ITGB1, and cell proliferation inhibition and cell apoptosis through 5-FUI and CDDP was abrogated in multicellular spheroids compared with monolayer cells.⁷ The ITGB1 inhibitory antibody prevented formation of multicellular spheroids and increased proliferation inhibition and apoptosis induction through suppression of FAK/Akt pathways. Mice tumors with ITGB1+ xenografts grew more rapidly than ITGB1- tumors.⁸ Resistance to treatment with radiation and cisplatin was increased considerably with overexpression of ITGB1 leading to EMT in ITGB1- tumors. Silencing ITGB1 expression significantly decreased resistance to irradiation and cisplatin treatment in ITGB1+ tumors. Conclusions: The studies indicate that ITGB1 is an important mediator in HCC cell proliferation and migration, regulation of EMT, multicellular drug resistance, and chemo/radiotherapy resistance. These results suggest that targeted therapy against ITGB1 has potential as a novel HCC therapeutic approach.

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