A piRNA-like Small RNA Induces Chemoresistance to Cisplatin-Based Therapy by Inhibiting Apoptosis in Lung Squamous Cell Carcinoma.
Lung cancer is the leading cause of cancer-related death worldwide. Although advanced drugs have benefitted patients, therapeutic success has largely been hampered because of rapid development of resistance. Here we report that PIWI-interacting RNA likes (piR-Ls), a novel type of functional sncRNAs, play key roles in chemoresistance to cisplatin (CDDP)-based chemotherapy in lung squamous cell carcinoma (LSCC). piR-L-138 was upregulated upon CDDP-based chemotherapy both in LSCC cells and in patient-derived xenograft (PDX) LSCC models. Further, targeting upregulated piR-L-138 led to increased apoptosis in CDDP-treated LSCC cells and LSCC xenograft mice treated with CDDP. In addition, piR-L-138 directly interacted with p60-MDM2 and inhibited CDDP-activated apoptosis in p53-mutated LSCC. We identified the upregulated piR-L-138 upon CDDP-based chemotherapy, confirmed the enhanced sensitivity of LSCC to agents by targeting the upregulated piR-L-138 both in vitro and in vivo, and revealed mechanisms underlying piR-L-138 in chemoresistance, bolstering a new emerging clinical modality where novel functional piR-Ls provide potential strategies to overcome chemoresistance for patients with LSCC.
Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, 650 W. Baltimore St., Baltimore, MD 21201, USA; Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Beijing Institute for Cancer Research, Beijing 100142, China.
Yuyan
Y
Wang
Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, 650 W. Baltimore St., Baltimore, MD 21201, USA.
Tyler
T
Gable
Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, 650 W. Baltimore St., Baltimore, MD 21201, USA.
Mark Z
MZ
Ma
Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA.
David
D
Clark
Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, 650 W. Baltimore St., Baltimore, MD 21201, USA; Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Beijing Institute for Cancer Research, Beijing 100142, China.
Jun
J
Zhao
Department of Thoracic Surgery, Lung Cancer Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.
Yi
Y
Zhang
Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China.
Wei
W
Liu
Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, 650 W. Baltimore St., Baltimore, MD 21201, USA.
Li
L
Mao
Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, 650 W. Baltimore St., Baltimore, MD 21201, USA. Electronic address: ymei@umaryland.edu.
Yuping
Y
Mei
chemoresistance; lung cancer; piRNA-likes; sncRNA